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Two series of heterocyclic steroidal pyrazolo[1,5- a ]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure–activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5- a ]pyrimidine might obviously affected by the β -hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, etc. In particular, compound 4c displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis. [Display omitted] • Novel steroidal pyrazolo[1,5- a ]pyrimidine derivatives. • Good cytotoxic activities compared with the 5-FU. • Compound 4c displayed highest inhibitory effect on the kinase of ALK with inhibition rate 40.63% at 10 μM. • The SARs analysis indicate hydrogen bond and hydrophobic force have a great influence on the activity of target derivatives. Two series of heterocyclic steroidal pyrazolo[1,5- a ]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized, and these compounds were screened for their potential antiproliferation activities. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure–activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5- a ]pyrimidine might be affected by the β -hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • GFS showed remarkable anti-melanin ability after citric acid heat treatment. • GFRS was first found to inhibit melanin deposition by promoting autophagy pathway. • Ginsenosides Rg 3 , Rg 5 and Rk 1 in GFRS might be the main material basis for their anti-melanin activity. GFRS is the conversion product of Panax ginseng Meyer berry after citric acid heat treatment, which is rich in rare ginsenosides. However, the anti-melanin role of GFRS in the regulation of skin pigmentation and its material basis remains unclear. To compare the anti-melanin activity before and after citric acid heat treatment, we determined the effects of GFS and GFRS on tyrosinase activity and melanin lever under α-MSH stimulation and found the potential anti-melanin effect of GFRS. Further, Western blot and immunofluorescence methods were used to reveal the mechanism by which GFRS detects anti-melanin activity by promoting autophagy flux levels. In zebrafish models, GFRS inhibited endogenous melanin and tyrosinase better than arbutin and promoted the accumulation of autophagy levels in vivo. To determine the material basis of the anti-melanin effect of GFRS, HPLC was used to isolate and prepare 12 ginsenosides from GFRS, and their activity evaluation and structure–activity relationship analysis were performed. The results showed that the inhibitory effect of GFRS on melanin was Rg 3 > Rg 5 > Rk 1 > Rd. Molecular docking showed that their docking fraction with mushroom tyrosinase was significantly better than that of arbutin, but the presence of C-20 glycosylation decreased the anti-melanin activity of Rd. To maximize the content of Rg 3 , Rg 5 , and Rk 1 , we optimized the process by using citric acid heat treatment of ginsenoside Rd and found that citric acid heat treatment at 100°C almost completely transformed Rd and obtained a high content of active ingredients. In summary, our data demonstrated that GFRS exerted anti-melanin effects by inducing autophagy. It was further revealed that Rg 3 , Rg 5 , and Rk 1 , as effective active components, could be enriched by the improved process of converting ginsenoside Rd by citric acid heat treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • The SARs of alkylides with extended sidechains at the 3-OH were elucidated. • The quinolone moiety exerts extra effects on enhancing antibacterial activity. • Compound 31f demonstrated inhibitory effects on both ribosomes and topoisomerases. • Compound 31f exhibited improved potency against constitutively resistant bacteria. Ketolides (3-keto) such as TE-802 and acylides (3- O -acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3- O -alkyl), we explored the structure–activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes , which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria. [ABSTRACT FROM AUTHOR]

Cephalostatins and ritterazines represent a distinctive class of marine-derived dimeric steroidal alkaloids with promising bioactivities and structural diversity, which is offering igniting interest in drug discovery endeavours. [Display omitted] Cephalostatins and ritterazines represent fascinating classes of dimeric marine derived steroidal alkaloids with unique chemical structures and promising biological activities. Originally isolated from marine tube worms and the tunicate Ritterella tokioka collected off the coast of Japan, cephalostatins and ritterazines display potent anticancer effects by inducing apoptosis, disrupting cell cycle progression, and targeting multiple molecular pathways. This review covers the chemistry and bioactivities of 45 cephalostatins and ritterazines from 1988 to 2024, highlighting their complex structures and medicinal contributions. With insights into their structure activity relationships (SAR). Key structural elements, such as the pyrazine ring and 5/6 spiroketal moieties, are found crucial for their biological effects, suggesting interactions with lipid membranes or hydrophobic protein domains. Additionally, the formation of oxocarbenium ions from spiroketal cleavage may enhance their potency by covalently modifying DNA. The pharmacokinetics, ADMET and Drug likeness properties of these steroidal alkaloids are thoroughly addressed. Drug likeness analysis shows that these compounds fit well with the Rule of 4 (Ro4) for Protein-Protein Interaction Drugs (PPIDs), underscoring their potential in this area. Ten compounds (20 , 27 , 33 , 34 , 39 , 40 , 41 , 42 , 43 , and 45) have demonstrated favourable pharmacokinetic and ADMET profiles, making them promising candidates for further research. Future efforts should focus on alternative administration routes, structural modifications, and innovative delivery systems, such as prodrugs and nanoparticles, to improve bioavailability and therapeutic effects. Advances in synthetic chemistry, mechanistic insights, and interdisciplinary collaborations will be essential for translating cephalostatins and ritterazines into effective anticancer therapies. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and synthesis of 16 novel gemini quaternary ammonium compounds with biocidal activity. • 5 novel compounds with wide-spectrum antimicrobial activity (bacteria, biofilm, fungi, virus), better solubility and lower cytotoxicity compare to commercially used octenidine dihydrochloride. • Compounds with increased polarity exhibited strong antifungal effect, with one compound being highly selective towards fungi. • Structure activity relationship study and in silico prediction. Since the discovery of antimicrobial agents, the misuse of antibiotics has led to the emergence of bacterial strains resistant to both antibiotics and common disinfectants like quaternary ammonium compounds (QACs). A new class, 'gemini' QACs, which contain two polar heads, has shown promise. Octenidine (OCT), a representative of this group, is effective against resistant microorganisms but has limitations such as low solubility and high cytotoxicity. In this study, we developed 16 novel OCT derivatives. These compounds were subjected to in silico screening to predict their membrane permeation. Testing against nosocomial bacterial strains (G+ and G-) and their biofilms revealed that most compounds were highly effective against G+ bacteria, while compounds 7 , 8 , and 10 – 12 were effective against G- bacteria. Notably, compounds 6 – 8 were significantly more effective than OCT and BAC standards across the bacterial panel. Compound 12 stood out due to its low cytotoxicity and broad-spectrum antimicrobial activity, comparable to OCT. It also demonstrated impressive antifungal activity. Compound 1 was highly selective to fungi and four times more effective than OCT without its cytotoxicity. Several compounds, including 4 , 6 , 8 , 9 , 10 , and 12 , showed strong virucidal activity against murine cytomegalovirus and herpes simplex virus 1. In conclusion, these gemini QACs, especially compound 12 , offer a promising alternative to current disinfectants, addressing emerging resistances with their enhanced antimicrobial, antifungal, and virucidal properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two novel phthalazinone PARP-1 inhibitor (DLC-1 – 46) and dual PARP-1/HDAC-1 inhibitors (DLC-47 – 63) were designed and synthesized. • The synthesized compounds were tested in vitro for their PARP-1 and PARP/HDAC-1 activities. • Most compounds showed high inhibitory activity on PARP-1 enzyme, especially DLC-1 – 6 , which showed IC 50 value <0.2 nM, which was better than the positive drug Olaparib. • Several compounds exhibited potent dual-target inhibitory activity, with DLC-49 displaying IC 50 values of 0.53 nM and 17 nM for PARP-1 and HDAC-1, respectively. • DLC-50 demonstrated the most potent anti-proliferative activity, with IC 50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells at 0.30, 2.70, and 2.41 μM. In recent years, poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) have emerged as significant targets in tumor therapy, garnering widespread attention. In this study, we designed and synthesized two novel phthalazinone PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors, named DLC-1 – 46 containing dithiocarboxylate fragments and DLC-47 – 63 containing hydroxamic acid fragments, and evaluated their inhibitory activities on enzymes and cells. Among the PARP-1 inhibitors, most compounds exhibited high inhibitory activity against the PARP-1 enzyme, with DLC-1 – 6 being particularly notable, showing IC 50 values <0.2 nM. Notably, DLC-1 demonstrated significant anti-proliferative activity, with IC 50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells reaching 0.08, 26.39, and 1.01 μM, respectively. Further investigation revealed that DLC-1 arrested MDA-MB-231 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Among the designed dual PARP-1/HDAC-1 inhibitors, several compounds exhibited potent dual-target inhibitory activity, with DLC-49 displaying IC 50 values of 0.53 nM and 17 nM for PARP-1 and HDAC-1, respectively. DLC-50 demonstrated the most potent anti-proliferative activity, with IC 50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells at 0.30, 2.70, and 2.41 μM, respectively. Cell cycle arrest and apoptosis assays indicated that DLC-50 arrested the cell cycle in the G2 phase and induced apoptosis in HCT-116 cells. Our findings present a novel avenue for further exploration of PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors. [ABSTRACT FROM AUTHOR]

Aurora kinases (AURKs)-a family of serine/threonine protein kinases consisting of AURK-A, AURK-B, and AURK-C, are critical regulators of chromosomal segregation, centrosome maturation, and cytokinesis during the cell cycle. Each kinase is activated via phosphorylation at unique threonine residues: Thr288 (AURK-A), Thr232 (AURK-B), and Thr195 (AURK-C). Activation of AURK-A and AURK-B through phosphorylation triggers a series of downstream signaling pathways, including RalA, NF-κB, p53, PLK1, BRCA1/BRCA2, H2AX, and Kif2C, as well as multiple transmembrane kinase receptors. Dysregulation of these pathways has been implicated in cancer development and progression, positioning AURKs as pivotal targets for anticancer drug research. Inhibition of AURKs has demonstrated significant efficacy in tumor growth suppression and induction of cancer cell death, thereby focusing recent research on the development of potent AURK inhibitors. This review provides an in-depth exploration of AURK inhibitors, discussing their biological activities, structure-activity relationships, selectivity profiles, and mechanisms of action. Notably, compounds 6, 27, and 16 exhibit potent AURK-A inhibition with IC 50 values of 1.7 nM, 11.83 nM, and 15 nM, respectively. Similarly, compounds 28, 16, and 7 demonstrate strong AURK-B inhibitory activity, with IC 50 values of 10.5 nM, 12 nM, and 14.09 nM, respectively. This comprehensive overview aims to support medicinal chemists in developing more potent, selective, and safe AURK inhibitors as potential anticancer therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

[Display omitted] The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure–activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • The structure and the NHEJ role of DNA-PK were elaborated. • The development progress of DNA-PK inhibitors and their SARs based on different scaffolds were analyzed. • The DNA-PK inhibitors under clinical trials were listed. The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel 25 arylaminonaphthols have been synthesized. • Biological evaluations of arylaminonaphthols revealing promising results in both antioxidant activity and BChE inhibition. • Theoretical calculations have been employed to understand the structure and properties of the synthesized compounds. • QSAR study has been used to establish relationships between chemical structures and biological activities. • Molecular docking has been performed to predict the binding interactions between arylaminonaphthols and the target enzymes. • Further research can focus on optimizing the chemical structures of the compounds to enhance their efficacy. A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N -ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r , 4u , 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC 50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure–activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g , 4q , 4r , 4u , and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings. [ABSTRACT FROM AUTHOR]

• Maintaining the geometry of B-ring is clearly crucial for bioactivity in the parent nucleus of lathyrane-type diterpenoid. • The acyloxy group at the 15-C position and the hydrophobic group at the 3-C are necessary for anti-inflammatory activity. • Compounds 15 and 17 demonstrated superior IL-1β-suppressed activation than other derivatives. • Compound 15 (EFL3) efficiently inhibits the IL-1β production related to the MSU-mediated inflammasome activation. Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 μM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1β related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1β and casepas-1 in the paw. To conclude, our findings reveal several potential key structure–activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention. [ABSTRACT FROM AUTHOR]

[Display omitted] • Antimicrobial peptides (AMPs) can have antibacterial, antifungal, antiviral and anti-inflammatory activities. • Net charge, hydrophobicity, and amino acid sequence can affect AMPs function. • Modification with other functional groups can also influence the AMPs activities. Proteins and peptides, as polypeptide chains, have usually got unique conformational structures for effective biological activity. Antimicrobial peptides (AMPs) are a group of bioactive peptides, which have been increasingly studied during recent years for their promising antibacterial, antifungal, antiviral and anti-inflammatory activity, as well as, other esteemed bioactivities. Numerous AMPs have been separated from a wide range of natural resources, or produced in vitro through chemical synthesis and recombinant protein expression. Natural AMPs have had limited clinical application due to several drawbacks, such as their short half-life due to protease degradation, lack of activity at physiological salt concentrations, toxicity to mammalian cells, and the absence of suitable methods of delivery for the AMPs that are targeted and sustained. The creation of synthetic analogs of AMPs would both avoid the drawbacks of the natural analogs and maintain or even increase the antimicrobial effectiveness. The structure–activity relationship of discovered AMPs or their derivatives facilitates the development of synthetic AMPs. This review discovered that the relationship between the activity of AMPs and their positive net charge, hydrophobicity, and amino acid sequence and the relationship between AMPs' function and other features like their topology, glycosylation, and halogenation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Opioids are the most effective drugs for the treatment of moderate to severe pain, and the µ-opioid receptor (MOR) is the most commonly used target of analgesic action in clinical practice and deserves to be studied in depth. • While many MOR drugs are in clinical studies, the fundamental problem with opioids—addiction and other side effects are still unresolved. • Although the hypothesis of G protein-biased agonists has been rejected, agonists with low intrinsic efficacy (e.g., TRV-130) are also one of the design strategies that can reduce the occurrence of adverse effects. • Selective action on different Gα subtypes, multiple agonists of opioid receptors, preferential activation of peripheral opioid receptors, targeting of allosteric sites of opioid receptors, and so on, will contribute to the discovery of efficient new MOR ligands. Opioids are currently the most effective and widely used painkillers in the world. Unfortunately, the clinical use of opioid analgesics is limited by serious adverse effects. Many researchers have been working on designing and optimizing structures in search of novel μ opioid receptor(MOR) agonists with improved analgesic activity and reduced incidence of adverse effects. There are many strategies to develop MOR drugs, mainly focusing on new low efficacy agonists (potentially G protein biased agonists), MOR agonists acting on different Gα subtype, targeting opioid receptors in the periphery, acting on multiple opioid receptor, and targeting allosteric sites of opioid receptors, and others. This review summarizes the design methods, clinical applications, and structure–activity relationships of small-molecule agonists for MOR based on these different design strategies, providing ideas for the development of safer novel opioid ligands with therapeutic potential. [ABSTRACT FROM AUTHOR]

[Display omitted] Janus kinases (JAKs), a kind of non-receptor tyrosine kinases, the function has been implicated in the regulation of cell proliferation, differentiation and apoptosis, immune, inflammatory response and malignancies. Among them, JAK1 represents an essential target for modulating cytokines involved in inflammation and immune function. Rheumatoid arthritis, atopic dermatitis, ulcerative colitis and psoriatic arthritis are areas where approved JAK1 drugs have been applied for the treatment. In the review, we provided a brief introduction to JAK1 inhibitors in market and clinical trials. The structures of high active JAK1 compounds (IC 50 ≤ 0.1 nM) were highlighted, with primary focus on structure–activity relationship and selectivity. Moreover, the druggability processes of approved drugs and high active compounds were analyzed. In addition, the issues involved in JAK1 compounds clinical application as well as strategies to surmount these challenges, were discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cyclin-dependent kinases (CDKs) are a family of protein-serine kinases. • Heterocyclic rings have demonstrated encouraging efficacy in inhibiting cyclin-dependent kinase activity. • CDK kinase inhibitors for the treatment of cancer. • Molecular interactions with receptor. Cyclin-dependent kinases (CDKs) constitute a vital family of protein-serine kinases, pivotal in regulating various cellular processes such as the cell cycle, metabolism, proteolysis, and neural functions. Dysregulation or overexpression of CDK kinases is directly linked to the development of cancer. However, the currently approved CDK inhibitors by the US FDA, such as palbociclib, ribociclib, Trilaciclib, Abemaciclib, etc., although effective, exhibit limited specificity and often lead to undesirable adverse effects. First and second-generation CDK inhibitors have not gained significant clinical interaction due to their high toxicity and lack of specificity. To address these challenges, a combined approach is being employed in the quest for newer CDK inhibitors aimed at mitigating toxicity and side effects associated with CDKIs. The discovery of therapeutic agents selectively targeting tumorous cells, such as CDK inhibitors, has demonstrated promise in treating various cancers, including breast cancer. Extensive literature reviews have facilitated the development of novel CDK inhibitors by combining medicinally preferred pyrimidine derivatives with other heterocyclic rings. Pyrimidine derivatives substituted with pyrazole, imidazole, benzamide, benzene sulfonamide, indole carbohydrazide, and other privileged heterocyclic rings have shown encouraging efficacy in inhibiting cyclin-dependent kinase activity. This review provides comprehensive data, including structure–activity relationship (SAR), anticancer activity, and kinetics studies of potent compounds. Additionally, molecular docking studies with compounds under clinical trial and patents filed on pyrimidine based CDK inhibitors in cancer treatment are included. This review serves as a valuable resource for further development of CDK kinase inhibitors for cancer treatment, offering insights into their efficacy, specificity, and potential clinical applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • 15 Low efficacy partial agonists of the mu-opioid receptor were synthesized. • 15 Compounds displayed high binding affinity to molecular target. • Compound 12 significantly blocked antinociceptive effects of morphine. • Compound 12 precipitated significantly less withdrawal than naloxone. • Substitutions at 5′-position of thiophene may be a solution to improve safety. The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT , a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood–brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5′-position of the thiophene ring were designed and their structure–activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management. [ABSTRACT FROM AUTHOR]

[Display omitted] • Total synthesis of palmarumycins B 7 and B 8. • Structure revision of palmarumycin B 8 based on the total synthesis, 2D NMR analysis and DFT calculation. • All compounds were examined the antifungal activity and discussed the structure–activity relationship. • Spirobisnaphthalene natural products are proved to have potential for new agrochemicals discovery. Palmarymycins B 8 (1), its regioisomer (2) and B 7 (3) were synthesized via 10-, 9-, and 11-steps in 6.5 %, 2.3 % and 0.54 % overall yields from chroman-4-one (4), 4-hydroxyindanone (12), and 2,5-dimethoxybenzaldehyde (20) as the starting materials, using benzyl protection, enol trimethylsilyl ether by TMSOTf, Rubottom oxidation and deprotection with hydrogenation under Pd/C catalyst as the key steps, respectively. Their structures were characterized by 1H, 13C NMR, COSY, HSQC, HMBC and HR-ESI-MS spectral data. The structure of palmarumycin B 8 was revised from 1 to 2 based on the total synthesis, 2D NMR analysis and DFT calculation. The antifungal assay results indicated that palmarumycin B 8 (1) showed moderate inhibitory activity against Phytophthora capsica. Compounds 15 and 16 exhibited excellent in vitro antifungal activities against P. capsica with EC 50 values of 2.17 and 8.50 μg/mL, respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • Demonstrating anti-cell proliferation activity and PARP-1 enzymatic inhibition activity in vitro. • Inhibiting colony formation and cell migration of HCT116 cells. • Inducing the cell apoptosis in HCT116 cells. • Upregulating the expression of apoptosis-related proteins in HCT116 cells. • Exhibiting anti-tumor effects in vivo. Poly(ADP-ribose) polymerase-1 (PARP-1) is a crucial member of DNA repair enzymes responsible for repairing DNA single-strand breaks. Developing PARP inhibitors based on synthetic lethality strategies is an effective approach for treating breast cancer and other diseases. In this study, a series of novel piperidine-based benzamide derivatives were designed and synthesized using structure-based drug design principles. The anticancer activities of these compounds were evaluated against five human cancer cell lines (MDA-MB-436, CAPAN-1, SW-620, HepG2, SKOV3, and PC3) and the preliminary structure–activity relationships were delineated. Among the compounds, 6a and 15d demonstrated potent antiproliferative effects against MDA-MB-436 cells with IC 50 values of 8.56 ± 1.07 μM and 6.99 ± 2.62 μM, respectively. Furthermore, both compounds exhibited excellent inhibitory activity against PARP-1, with IC 50 values of 8.33 nM and 12.02 nM, respectively. Mechanistic investigations revealed that 6a and 15d effectively inhibited colony formation and cell migration of HCT116 cells. Moreover, they induced apoptosis by upregulating the expression of Bax and cleaved Caspase-3, while downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. Based on its impressive pharmacodynamic data in vitro, we conducted a study to evaluate the efficacy of 15d in a xenograft tumor model in mice when used in combination with cytotoxic agents. Collectively, these findings suggest that 15d could be promising drug candidates worthy of further investigation. [ABSTRACT FROM AUTHOR]

[Display omitted] • The thieno[3,2- d ]pyrimidine scaffold offered a new design for CDK7 inhibitors. • Compound 20 demonstrated prominent CDK7 inhibition and cellular potency. • Compound 20 showed desirable pharmacokinetic properties. The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2- d ]pyrimidine-based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2- d ]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure–activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of 24 sulfonamide-based ferroptosis inhibitors. • Compound 23b has strong ferroptosis inhibitory activity (EC 50 = 0.001 μM), low cytotoxicity and low hERG binding affinity (IC 50 > 30 μM). • Compound 23b did not show significant toxicity in vivo or in vitro. Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure–activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC 50 = 0.001 μM) and demonstrated a low hERG inhibition activity (IC 50 > 30 μM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b , a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation. [ABSTRACT FROM AUTHOR]

[Display omitted] • New Ethyl 2-thioalkyl-4-phenyl-6-(cycloamine)nicotinate derivatives were synthesized in high yield based on thiopyranthione and fully characterized by physico-chemical methods. • The biological spectrum of the new synthesized compounds have been predicted and evaluated. • Neurotropic activity (in vivo) has been evaluated and make SAR based on anticonvulsant, anxiolytic and antidepressant activities. Pyridine and its derivatives play a vital role in medicinal chemistry, serving as key scaffolds for drugs. The ability to bind to biological targets makes pyridine compounds significant, sparking interest in creating new pyridine-based drugs. Thus, the purpose of the research is to synthesize new thioalkyl derivatives of pyridine, predict their biological spectrum, study their psychotropic properties, and based on these findings, perform structure–activity relationships to assess pharmacophore functional groups. Classical organic methods were employed for synthesizing new thioalkyl derivatives of pyridine, with a multifaceted pharmacological profiles. Various software packages and methods were employed to evaluate the biological spectrum of the newly synthesized compounds. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. Effective synthetic methods for 6-amino-4-phenyl-2-thio-2 H -thiopyran-5-carboxylic acid ethyl ester, 2-amino substituted thiopyridine derivatives and 6-cycloamino-2-thioalkyl-4-phenylnicotinate derivatives were obtained in high yield. Predicted biological spectra and pharmacokinetic data indicated high gastrointestinal absorption and low blood–brain barrier passage for most compounds and demonstrated potential various biological effects, particularly psychotropic properties. Studied compounds demonstrated high anticonvulsant activity through antagonism with pentylenetetrazole. They exhibited low toxicity without inducing muscle relaxation in the studied doses. In psychotropic studies, the compounds displayed activating, sedative, and anxiolytic effects. Notably, the 6-amino-2-thioalkyl-4-phenylnicotinate derivatives demonstrated significant anxiolytic activity (about four times more compared to diazepam). They also exhibited pronounced sedative effects. Ethyl 2-({2-[(diphenylmethyl)amino]-2-oxoethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate exhibited anxiolytic activity even two times greater than diazepam. Moreover, all studied compounds showed statistically significant antidepressant effects. Noteworthy ethyl 2-({2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate showcasing its unique psychotropic effect. The selected compounds demonstrate anticonvulsant properties, activating behavior, and anxiolytic effects, while simultaneously exhibiting antidepressant effects and these compounds as promising candidates for further exploration in the development of therapeutics with a broad spectrum of neuropsychiatric applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dinucleoside polyphosphates (NpxNs) were studied as human adenylate kinase isoenzyme 1 (hAK1) inhibitors. • Docking studies on hAK1-NpxN interactions mainly agree with the experimental results. • For three dinucleoside polyphosphates, an IC 50 value of less than 1 µM was reported. • Two PLS-regression-based QSAR models were built for human AK1. Adenylate kinase (AK) plays a crucial role in the metabolic monitoring of cellular adenine nucleotide homeostasis by catalyzing the reversible transfer of a phosphate group between ATP and AMP, yielding two ADP molecules. By regulating the nucleotide levels and energy metabolism, the enzyme is considered a disease modifier and potential therapeutic target for various human diseases, including malignancies and inflammatory and neurodegenerative disorders. However, lacking approved drugs targeting AK hinders broad studies on this enzyme's pathological importance and therapeutic potential. In this work, we determined the effect of a series of dinucleoside polyphosphate derivatives, commercially available (11 compounds) and newly synthesized (8 compounds), on the catalytic activity of human adenylate kinase isoenzyme 1 (hAK1). The tested compounds belonged to the following groups: (1) diadenosine polyphosphates with different phosphate chain lengths, (2) base-modified derivatives, and (3) phosphate-modified derivatives. We found that all the investigated compounds inhibited the catalytic activity of hAK1, yet with different efficiencies. Three dinucleoside polyphosphates showed IC 50 values below 1 µM, and the most significant inhibitory effect was observed for P 1-(5′-adenosyl) P5-(5′-adenosyl) pentaphosphate (Ap 5 A). To understand the observed differences in the inhibition efficiency of the tested dinucleoside polyphosphates, the molecular docking of these compounds to hAK1 was performed. Finally, we conducted a quantitative structure–activity relationship (QSAR) analysis to establish a computational prediction model for hAK1 modulators. Two PLS-regression-based models were built using kinetic data obtained from the AK1 activity analysis performed in both directions of the enzymatic reaction. Model 1 (AMP and ATP synthesis) had a good prediction power (R2 = 0.931, Q2 = 0.854, and MAE = 0.286), while Model 2 (ADP synthesis) exhibited a moderate quality (R2 = 0.913, Q2 = 0.848, and MAE = 0.370). These studies can help better understand the interactions between dinucleoside polyphosphates and adenylate kinase to attain more effective and selective inhibitors in the future. [ABSTRACT FROM AUTHOR]

[Display omitted] • Five pairs of novel merosesquiterpenoid enantiomers were isolated and identified. • Dauresorcinol A (1) possesses an unprecedented methyl-shifted merosesquiterpenoid carbon skeleton. • Dauresorcinol B (2) bears a novel caged merosesquiterpenoid carbon skeleton. • (+)/(−)- 1 and 3 − 5 showed more potent α -glucosidase inhibitory activity than acarbose. • The structure−activity relationships of isolates were discussed. Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A−E (1 − 5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh 2 (OCOCF 3) 4 -induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1 − 5 are proposed involving key oxa-electrocyclization and Wagner−Meerwein rearrangement reactions. (+)/(−)- 1 and 3 − 5 showed potent α -glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α -glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α -glycosidase inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • The importance of saccharides in the antibacterial activity and resistance elimination is analyzed. • The antibacterial activity and SAR of agents containing mono- or di- or oligosaccharide are summarized. • Strategies for the development of novel antimicrobial agents and avoidance of resistance are proposed. Bacterial infections are the second leading cause of death worldwide, and the evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens exacerbate the threat crisis. Carbohydrates participate in bacterial infection, drug resistance and the process of host immune regulation. Numerous antimicrobials derived from carbohydrates or contained carbohydrate scaffolds that are conducive to an increase in pathogenic bacteria targeting, the physicochemical properties and druggability profiles. In the paper, according to the type and number of sugar residues contained in antimicrobial molecules collected from the literatures ranging from 2014 to 2024, the antimicrobial activities, action mechanisms and structure–activity relationships were delineated and summarized, for purpose to provide the guiding template to select the type and size of sugars in the design of oligosaccharide-based antimicrobials to fight the looming antibiotic resistance crisis. [ABSTRACT FROM AUTHOR]

By using pharmacophores and virtual screening, the lead compound SH-05 with a unique phosphate motif was identified. Subsequently, a series of compounds 3a-3z were synthesized and characterized. Bioactivity assay and toxicity prediction revealed that compound 3g may be a promising antiviral agent. [Display omitted] • TMV-CP based rational design of anti-viral agents was firstly conducted. • α-Amide phosphate derivative is screen out as a lead compound. • A series of phosphate derivative was synthesized based on SH-05. • The synthesized compound 3 g showed strong interaction with TMV-CP. • The found pharmacophore model could be used for discovery of anti-viral agent. The tobacco mosaic virus coat protein (TMV-CP) is indispensable for the virus's replication, movement and transmission, as well as for the host plant's immune system to recognize it. It constitutes the outermost layer of the virus particle, and serves as an essential component of the virus structure. TMV-CP is essential for initiating and extending viral assembly, playing a crucial role in the self-assembly process of Tobacco Mosaic Virus (TMV). This research employed TMV-CP as a primary target for virtual screening, from which a library of 43,417 compounds was sourced and SH-05 was chosen as the lead compound. Consequently, a series of α-amide phosphate derivatives were designed and synthesized, exhibiting remarkable anti-TMV efficacy. The synthesized compounds were found to be beneficial in treating TMV, with compound 3 g displaying a slightly better curative effect than Ningnanmycin (NNM) (EC 50 = 304.54 µg/mL) at an EC 50 of 291.9 µg/mL. Additionally, 3 g exhibited comparable inactivation activity (EC 50 = 63.2 µg/mL) to NNM (EC 50 = 67.5 µg/mL) and similar protective activity (EC 50 = 228.9 µg/mL) to NNM (EC 50 = 219.7 µg/mL). Microscale thermal analysis revealed that the binding of 3 g (K d = 4.5 ± 1.9 µM) to TMV-CP showed the same level with NNM (K d = 5.5 ± 2.6 µM). Results from transmission electron microscopy indicated that 3 g could disrupt the structure of TMV virus particles. The toxicity prediction indicated that 3 g was low toxicity. Molecular docking showed that 3 g interacted with TMV-CP through hydrogen bond, attractive charge interaction and π-Cation interaction. This research provided a novel α-amide phosphate structure target TMV-CP, which may help the discovery of new anti-TMV agents in the future. [ABSTRACT FROM AUTHOR]

[Display omitted] • 1b and 1f showed 2.9 ∼ 4.5-fold more potent TRPV4 inhibition activity than RN9893. • The IC 50 s of 1b and 1f against TRPV4 are 0.71 ± 0.21 and 0.46 ± 0.08 μM, respectively. • 1b and 1f significantly alleviated acute lung injury symptoms in mice. • RN9893 analogues are potent TRPV4 inhibitors. RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC 50 = 0.71 ± 0.21 μM and 0.46 ± 0.08 μM, respectively) in vitro , in comparison to RN-9893 (IC 50 = 2.07 ± 0.90 μM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 μM, against RN-9893′s 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activity was evaluated. • The System SAR study discovered a promising compound 33c , which has a strong inhibitory effect on ASK1. • The cytotoxicity, oil red O staining, biochemical analysis experiment, Western blotting, and molecular docking of 33c were also carried out. Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c , which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH. [ABSTRACT FROM AUTHOR]

This review provides a comprehensive overview of non-peptidic SARS-CoV-2 Mpro inhibitors, including non-covalent inhibitors with various privileged fragments and covalent inhibitors with various covalent warheads. [Display omitted] The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (Mpro) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body. Among the SARS-CoV-2 Mpro inhibitors, non-peptidic compounds hold promising prospects owing to their excellent antiviral activity and improved metabolic stability. In this review, we offer an overview of research progress concerning non-peptidic SARS-CoV-2 Mpro inhibitors since 2020. The efforts delved into molecular structures, structure–activity relationships (SARs), biological activity, and binding modes of these inhibitors with Mpro. This review aims to provide valuable clues and insights for the development of anti-SARS-CoV-2 agents as well as broad-spectrum coronavirus Mpro inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] Activin receptor‑like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-β (TGF-β) family. (TGF-β) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation within the signaling pathway can cause variety of diseases, such as fibrosis, cardiovascular disease, and especially cancer, rendering ALK5 a potential drug target. Hence, various small molecules have been designed and synthesized as potent ALK5 inhibitors. In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure–activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles. [ABSTRACT FROM AUTHOR]

[Display omitted] • Naturally occurring houttuynin and its sulfonate derivatives were found to be potential novel NDM-1 inhibitors. • Sodium new houttuyfonate (SNH), a traditional Chinese medicine, is identified a partially reversible NDM-1 inhibitor. • SNH-2 to SNH-5 provide inhibitory activities at micromole level against NDM-1. Discovering novel NDM-1 inhibitors is an urgent task for treatment of 'superbug' infectious diseases. In this study, we found that naturally occurring houttuynin and its sulfonate derivatives might be effective NDM-1 inhibitors with novel mechanism, i.e. the attribute of partially covalent inhibition of sulfonate derivatives of houttuynin against NDM-1. Primary structure–activity relationship study showed that both the long aliphatic side chain and the warhead of aldehyde group are vital for the efficiency against NDM-1. The homologs with longer chains (SNH-2 to SNH-5) displayed stronger inhibitory activities with IC 50 range of 1.1–1.5 μM, while the shorter chain the weaker inhibition. Further synergistic experiments in cell level confirmed that all these 4 compounds (at 32 μg/mL) recovered the antibacterial activity of meropenem (MER) against E. coli BL21/pET15b- bla NDM-1. [ABSTRACT FROM AUTHOR]

[Display omitted] • Screening of a DNA-encoded library from the DELopen platform with 3 isoforms of OGT yielded several binders. • Selecting a few binders for inhibition yielded hits with micromolar inhibition. • Modeling revealed that two new chemotypes of inhibitors were identified. • Studies with derivatives of the hits provided a direction for further optimization. Finding potent inhibitors of O-GlcNAc transferase (OGT) has proven to be a challenge, especially because the diversity of published inhibitors is low. The large majority of available OGT inhibitors are uridine-based or uridine-like compounds that mimic the main interactions of glycosyl donor UDP-GlcNAc with the enzyme. Until recently, screening of DNA-encoded libraries for discovering hits against protein targets was dedicated to a few laboratories around the world, but has become accessible to wider public with the recent launch of the DELopen platform. Here we report the results and follow-up of a DNA-encoded library screening by using the DELopen platform. This led to the discovery of two new hits with structural features not resembling UDP. Small focused libraries bearing those two scaffolds were made, leading to low micromolar inhibition of OGT and elucidation of their structure–activity relationship. [ABSTRACT FROM AUTHOR]

[Display omitted] • The SAR of antifungal oleanolic acid-type saponins from P. chinensis were revealed. • 23-Hydroxyl group and free carboxyl at C-28 were essential for antifungal activity. • A disaccharide or trisaccharide moiety at C-3 was favorable for antifungal activity. • Typical saponin PB3 downregulated Bcr1-dependent adhesins pathway in C. albicans. • PB3 induced the endogenous ROS-mediated oxidative damage leading to cell death. In the course of our investigations of antifungal natural products, the structure–activity relationship and antifungal activities of oleanolic acid-type saponins (1 – 28) from Pulsatilla chinensis against human and plant pathogenic fungi were elucidated. The analysis of structure–activity relationship of oleanolic acid-type saponins showed that the free carboxyl at C-28 was essential for their antifungal activities; the free hydroxyl group at the C-23 site of oleanolic acid-type saponins played a crucial role in their antifungal activities; the oligosaccharide chain at C-3 oleanolic acid-type saponins showed significant effects on antifungal efficacy and a disaccharide or trisaccharide moiety at position C-3 displayed optimal antifungal activity. The typical saponin pulchinenoside B3 (16 , PB3) displayed satisfactory antifungal activity against human and plant pathogenic fungi, especially, C. albicans with an MIC value of 12.5 μg/mL. Furthermore, PB3 could inhibit the biofilm formation of C. albicans through downregulating the expression of the integrated network of biofilm formation-associated transcription factors (Bcr1 Efg1, Ndt80, Brg1, Rob1 and Tec1) and adhesion-related target genes (HWP1 , ALS1 , and ALS3). Meanwhile, we found that PB3 could effectively destroy the mature biofilm of C. albicans by the oxidative damage and inducing mitochondria-mediated apoptosis in cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel rosmarinic acid derivatives against MRSA were developed. • Compound RA-N8 exhibited the most potent antibacterial ability against MRSA (BAA41 and 43300) and killed E. coli when used in combination with PMBN. • Compound RA-N8 showed very low cytotoxicity to the human normal cell line (HFF1) and a weak hemolytic effect at the minimum inhibitory concentration. • SYTOX Green, LIVE/DEAD fluorescence, and SEM assays validated that compound RA-N8 eliminated bacteria by targeting bacterial cell membranes. • The resistance development test proved that it was difficult for compound RA-N8 to generate drug resistance in wild-type S. aureus. • Compound RA-N8 presented potent anti-biofilm ability and could destroy established biofilm. Twenty-seven rosmarinic acid derivatives were synthesized, among which compound RA-N8 exhibited the most potent antibacterial ability. The minimum inhibition concentration of RA-N8 against both S. aureus (ATCC 29213) and MRSA (ATCC BAA41 and ATCC 43300) was found to be 6 μg/mL, and RA-N8 killed E. coli (ATCC 25922) at 3 μg/mL in the presence of polymyxin B nonapeptide (PMBN) which increased the permeability of E. coli. RA-N8 exhibited a weak hemolytic effect at the minimum inhibitory concentration. SYTOX Green assay, SEM, and LIVE/DEAD fluorescence staining assay proved that the mode of action of RA-N8 is targeting bacterial cell membranes. Furthermore, no resistance in wildtype S. aureus developed after incubation with RA-N8 for 20 passages. Cytotoxicity studies further demonstrated that RA-N8 is non-toxic to the human normal cell line (HFF1). RA-N8 also exerted potent inhibitory ability against biofilm formation of S. aureus and even collapsed the shaped biofilm. [ABSTRACT FROM AUTHOR]

[Display omitted] • An activated ester of HOBt is converted to an ether by intramolecular nucleophilic substitution. • Arylacryl amide 9d protects against cisplatin-induced AKI through inhibiting inflammation via TLR4/STING/NF-κB pathway. • 9d improved renal tubular damage by reducing NF-κB phosphorylation level and promoting tubular epithelial cell proliferation. • 9d reduced the release of inflammatory factors (IL-1β, IL-6 and TNF-α) and the expression of KIM-1 proteins in vivo. Arylpropionic ester scaffold was found as anti-inflammatory agents for the treatment and prevention of acute kidney injury (AKI). To further study the structure–activity relationship (SAR) of this scaffold, a series of acryl amides were designed, synthesized, and evaluated their anti-inflammation. Of these, compound 9d displayed the protective effect on renal tubular epithelial cells to significantly enhance the survival rate through inhibiting NF-κB phosphorylation and promoting cell proliferation in cisplatin-induced HK2 cells. Furthermore, 9d can interact with TLR4 to inhibit TLR4/STING/NF-κB pathway in the RAW264.7 cell. In vivo AKI mice model, 9d significantly downregulated the level of serum creatinine (Scr), blood urea nitrogen (BUN) and the inflammatory factors (IL-1β, IL-6, TNF-α) to improve kidney function. Morphological and KIM-1 analyses showed that 9d alleviated cisplatin-induced tubular damage. In a word, 9d was a promising lead compound for preventive and therapeutic of AKI. [ABSTRACT FROM AUTHOR]

[Display omitted] • The biological and phytochemical study on Croton lauioides was investigated firstly. • 23 conjugated enone-type components, including nine undescribed ones were obtained. • Guaianes with aromatic moiety exhibited potent NO-suppression effects in BV-2 cells. • Compound 5 showed promising anti-neuroinflammatory effect through the NF- κ B pathway. In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1 – 23), including nine previously unknown sesquiterpenoid derivatives (1 – 4 , 9 – 10 , 12 – 14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2 – 7 are non-benzenoid aromatics featuring a tropone function, while 9 – 11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC 50 value of 0.14 ± 0.04 μM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF- α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF- α , COX-2. In mechanism, 5 could prevented activation of NF- κ B pathway by suppressing phosphorylation of p65 and I κ B- α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of 3-substituted indole derivatives were synthesised and evaluated antifungal activities in vitro. • Compound 1 showed the best antifungal activities against drug-resistant Candida albicans. • The compound 1 was selected to study the anti-Candida albicans. mechanism. In this work, we synthesized a series of indole derivatives to cope with the current increasing fungal infections caused by drug-resistant Candida albicans. All compounds were evaluated for antifungal activities against Candida albicans in vitro , and the structure–activity relationships (SARs) were analyzed. The results indicated that indole derivatives used either alone or in combination with fluconazole showed good activities against fluconazole-resistant Candida albicans. Further mechanisms studies demonstrated that compound 1 could inhibit yeast-to-hypha transition and biofilm formation of Candida albicans , increase the activity of the efflux pump, the damage of mitochondrial function, and the decrease of intracellular ATP content. In vivo studies, further proved the anti- Candida albicans activity of compound 1 by histological observation. Therefore, compound 1 could be considered as a novel antifungal agent. [ABSTRACT FROM AUTHOR]

[Display omitted] • The investigation on the antioxidant and digestive enzymes inhibition activity of phenylpropanoids, as well as their structure–activity relationship was conducted for the first time. • The potential of phenylpropanoids compounds as dual inhibitors for suppressing α-glucosidase and lipase was evaluated innovatively. • Comprehensive technologies have been employed for probing the inhibition mechanism of phenylpropanoids against both digestive enzymes. Phenylpropanoids (PPs), a group of natural compounds characterized by one or more C6-C3 units, have exhibited considerable potential in addressing metabolic disease. However, the comprehensive investigation on the relationship of compound structures and involved activity, along with the action mechanisms on the drug target is absent. This study aimed to evaluate the antioxidant and inhibitory activities of 16 PPs against two digestive enzymes, including α-glucosidase and pancreatic lipase, explore the structure–activity relationships and elucidate the mechanisms underlying enzyme inhibition. The findings revealed the similarities in the rules governing antioxidant and enzyme inhibitory activities of PPs. Specifically, the introduction of hydroxyl groups generally exerted positive effects on the activities, while the further methoxylation and glycosylation were observed to be unfavorable. Among the studied PPs, esculetin exhibited the most potent antioxidant activity and dual enzymes inhibition potential, displaying IC 50 values of 0.017 and 0.0428 mM for DPPH and ABTS radicals scavenging, as well as 1.36 and 6.67 mM for α-glucosidase and lipase inhibition, respectively. Quantification analysis indicated esculetin bound on both α-glucosidase and lipase successfully by a mixed-type mode. Further analyses by UV–Vis, FT-IR, fluorescence spectra, surface hydrophobicity, SEM, and molecular docking elucidated that esculetin could bind on the catalytic or non-catalytic sites of enzymes to form complex, impacting the normal spatial conformation for hydrolyzing the substrate, thus exhibiting the weakened activity. These results may shed light on the utilization value of natural PPs for the management of hyperglycemia and hyperlipemia, and afford the theoretical basis for designing drugs with stronger inhibition against the dual digestive enzymes based on esculetin. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel Topo I inhibitors were designed, synthesized and bio-evaluated. • A crucial intermediate has been developed: matrine diazo. • Thirty-two chiral compounds with a single configuration were synthesized. • Compound Q12 significantly inhibits the growth of HepG2 tumors in vivo while demonstrating high safety. Since the thalidomide incident, research on chiral drugs has escalated immensely. Differences in drug configuration can lead to significant variations in therapeutic efficacy. Matrine, a natural product esteemed for its low toxicity and high water solubility, has garnered significant attention in research endeavors. Nonetheless, its precise target has proven elusive. In this study, we designed and synthesized a novel chiral matrine derivative. Their cytotoxicity against three types of tumor cells was assessed. Comparing the newly synthesized derivatives to the parent matrine, most compounds exhibited significantly enhanced inhibitory effects on cancer cells. Among them, Q12 exhibited the highest activity, with IC 50 values of 8.31 μM against rat glioma cells C6, 6.3 μM against human liver cancer cells HepG2 and 7.14 μM against human gastric cancer cells HGC-27, meanwhile showing low toxicity. Based on IC 50 values, we constructed a preliminary structure–activity relationship (SAR). Compound Q12 significantly suppressed the cloning and migration of HepG2 cells. Further mechanistic studies indicated that Q12 inhibited Topo I in HepG2 cells, leading to DNA damage, induction of G0/G1 cell cycle arrest and ultimately causing apoptosis. The molecular docking experiments provided a rational binding mode of Q12 with the Topo I-DNA complex. In vivo, experiments demonstrated that Q12 exhibited a higher tumor growth inhibition rate (TGI) compared to the positive control drug Lenvatinib, while maintaining good safety. In summary, it suggests that Topo I might be a potential target for matrine and Q12 represents a promising candidate for cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • For the management of T2DM, DPP-4 inhibitors are well established therapeutics. • Advantages include ability to improve nephropathy, retinopathy, cardiovascular complications and glucose lowering effect. • More than twelve agents with diverse chemical nuclei have been approved by FDA. • SAR analysis suggests introduction of appropriate substitutions to achieve the desired selectivity. Diabetes mellitus (DM) is one of the largest public health problems worldwide and in the last decades various therapeutic targets have been investigated. For the treatment of type-2 DM (T2DM), dipeptidyl peptidase-4 (DPP-4) is one of the well reported target and has established safety in terms of cardiovascular complexicity. Preclinical and clinical studies using DPP-4 inhibitors have demonstrated its safety and effectiveness and have lesser risk of associated hypoglycaemic effect making it suitable for elderly patients. FDA has approved a number of structurally diverse DPP-4 inhibitors for clinical use. The present manuscript aims to focus on the well reported hybrid and non-hybrid analogues and their structural activity relationship (SAR) studies. It aims to provide structural insights for this class of compounds pertaining to favourable applicability of selective DPP-4 inhibitors in the treatment of T2DM. [ABSTRACT FROM AUTHOR]

PD-L1, IDO1, and TGF-β immunosuppressive signaling pathways are upregulated in tumor cells. Small-molecule immune modulators are exhibited in the picture. [Display omitted] In recent years, tumor immunotherapy, aimed at increasing the activity of immune cells and reducing immunosuppressive effects, has attracted wide attention. Among them, immune checkpoint blocking (ICB) is the most commonly explored therapeutic approach. All approved immune checkpoint inhibitors (ICIs) are clinically effective monoclonal antibodies (mAbs). Compared with biological agents, small-molecule drugs have many unique advantages in tumor immunotherapy. Therefore, they also play an important role. Immunosuppressive signals such as PD-L1, IDO1, and TGF-β, etc. overexpressed in tumor cells form the tumor immunosuppressive microenvironment. In addition, the efficacy of multi-pathway combined immunotherapy has also been reported and verified. Here, we mainly reviewed the mechanism of tumor immunotherapy, analyzed the research status of small-molecule modulators, and discussed drug candidates' structure–activity relationship (SAR). It provides more opportunities for further research to design more immune small-molecule modulators with novel structures. [ABSTRACT FROM AUTHOR]

[Display omitted] • 37 β -carboline derivatives were synthesized, with monomer M3 and dimer D4 possessing the selective activity and higher cytotoxicity in tumor cells than in normal cells. • The antitumor mechanism of M3 and D4 was explored, identifying CDK2 and DNA as potential key targets. • M3 and D4 interacts with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes. • M3 , as a dual-pocket inhibitor of CDK2, is a promising framework for the rational design of next-generation CDK2 inhibitors. β -Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized β -carbolines exert excellent antitumor activity. In the present research, 37 β -carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. β -Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC 50 = 1.44 ± 1.10 μM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC 50 = 2.84 ± 0.73 μM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3 -treated A549 cells and D4 -treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fifteen new hecogenin–triphenylphosphonium conjugates were designed and synthesized. • The conjugates were screened for their antiproliferative activities. • Compound 3c exhibited the best inhibitory activity against human gastric cancer MKN45 cells. • Compound 3c induced MKN45 cells apoptosis through mitochondrial pathway. • Compound 3c inhibited MKN45 cells proliferation in an in vivo zebrafish xenograft model. Hecogenin (HCG), a steroidal sapogenin, possesses good antitumor properties. However, the application of HCG for cancer treatment has been hindered primarily by its moderate potency. In this study, we incorporated triphenylphosphonium cation (TPP+) at the C-3 and C-12 positions through different lengths of alkyl chains to target mitochondria and enhance the efficacy and selectivity of the parent compound. Cytotoxicity screening revealed that most of the target compounds exhibited potent antiproliferative activity against five human cancer cell lines (MKN45, A549, HCT-116, MCF-7, and HepG2). Structure-activity relationship studies indicated that the TPP+ group significantly enhanced the antiproliferative potency of HCG. Among these compounds, 3c demonstrated remarkable potency against MKN45 cells with an IC 50 value of 0.48 μM, significantly more effective than its parent compound HCG (IC 50 > 100 μM). Further investigations into the mechanism of action revealed that 3c induced apoptosis of MKN45 cells through the mitochondrial pathway. In a zebrafish xenograft model, 3c inhibited the proliferation of MKN45 cells. Overall, these results suggest that 3c , with potent antiproliferative activity, may serve as a valuable scaffold for developing new antitumor agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • 32 diterpenoids with multi -skeletons were isolated from Euphorbia peplus. • Six diterpenoids exhibit significant anti-inflammatory activity. • Compound 13 can suppress the activation of NF-κB and MAPK signaling pathways. • Compound 21 showed moderated cytotoxic activity. Phytochemical investigation into the medium polar fraction of the ethanol extract of Euphorbia peplus led to the identification of 32 diterpenoids with five structural types. Compounds 1 – 5 and 7 – 11 are reported for the first time, while the configuration of 6,7-epoxy group of 6 was revised to be β -oriented. Compounds 1 – 5 feature a rare structural variation of the double bond at Δ1 migrating to Δ1(10) in the tigliane-type diterpenoid family. Biologically, compound 21 was found to be the only one to show moderate cytotoxic activity, associated with the presence of a benzoyloxy residue at C-16. Besides, compounds 4 , 8 , 12 , 13 , 16 , and 19 show significant inhibitory activities against NO production induced by LPS in RAW264.7 macrophage cells, with IC 50 values within 2–5 μM. Structure-activity relationship (SAR) analysis revealed that the ingenane-type diterpenoids have the best anti-inflammatory activity, and the esterification at 3-OH or 5-OH is crucial. Further biological researches demonstrated that 13 , the predominant metabolite in this plant, exerts anti-inflammatory effects by blocking the activation of NF-κB and MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

[Display omitted] Alzheimer's disease (AD) is the most common form of dementia affecting specifically older population. AD is an irreversible neurodegenerative CNS disorder associated with complex pathophysiology. Presently, the USFDA has approved only four drugs viz. Donepezil, Rivastigmine, Memantine, and Galantamine for the treatment of AD. These drugs exhibit their neuroprotective effects either by inhibiting cholinesterase enzyme (ChE) or N -methyl- d -aspartate (NMDA) receptor. However, the conventional therapy "one target, one molecule" has failed to provide promising therapeutic effects due to the multifactorial nature of AD. This triggered the development of a novel strategy called Multi-Target Directed Ligand (MTDL) which involved designing one molecule that acts on multiple targets simultaneously. The present review discusses the detailed pathology involved in AD and the various MTDL design strategies bearing different heterocycles, in vitro and in vivo activities of the compounds, and their corresponding structure–activity relationships. This knowledge will allow us to identify and design more effective MTDLs for the treatment of AD. [ABSTRACT FROM AUTHOR]

[Display omitted] Nucleobases serve as essential molecular frameworks present in both natural and synthetic compounds that exhibit notable antiviral activity. Through molecular modifications, novel nucleobase-containing drugs (NCDs) have been developed, exhibiting enhanced antiviral activity against a wide range of viruses, including the recently emerged SARS‑CoV‑2. This article provides a detailed examination of the significant advancements in NCDs from 2015 till current, encompassing various aspects concerning their mechanisms of action, pharmacology and antiviral properties. Additionally, the article discusses antiviral prodrugs relevant to the scope of this review. It fills in the knowledge gap by examining the structure–activity relationship and trend of NCDs as therapeutics against a diverse range of viral diseases, either as approved drugs, clinical candidates or as early-stage development prospects. Moreover, the article highlights on the status of this field of study and addresses the prevailing limitations encountered. [ABSTRACT FROM AUTHOR]

[Display omitted] • The structure–activity relationship of the C20 position of betulinic acid was explored. • Reducing systemic exposure by introducing kinetophores to betulinic acid scaffold. • The plasma distribution of 22-Na and 30-Na were 1029-fold and 1553-fold lower than the corresponding precursor 11d-Na , respectively. • 22-Na and 30-Na effectively alleviated the gallbladder side effects, showed satisfactory gallbladder safety after 7-day administration. The pleiotropic effects of TGR5 make it an appealing target for intervention of metabolic and inflammatory disorders, but systemic activation of TGR5 faces challenges of on-target side effects, especially gallbladder filling. Gut-restricted agonists were proved to be sufficient to circumvent these side effects, but extremely low systemic exposure may not be effective in activating TGR5 since it is located on the basolateral membrane. Herein, to balance potency and physicochemical properties, a series of gut-restricted TGR5 agonists with diversified kinetophores had been designed and synthesized. Compound 22-Na exhibited significant antidiabetic effect, and showed favorable gallbladder safety after 7 days of oral administration in humanized TGR5H88Y mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • The anticancer activity of Coelenterazine and Coelenteramine analogs was studied. • These two types of analogs showed differences in anticancer activity; • Coelenterazine analogs showed time-independent and safer activity. • Their activity appears to be correlated with their chemiluminescence properties. • Coelenteramine analogs showed time-dependent and moiety-dependent activity. Cancer is still one of the most challenging diseases to treat, making the pursuit for novel molecules with potential anticancer activity an important research topic. Herein, we have performed a comparative investigation into the anticancer activity of analogs of marine coelenterazine and coelenteramine. The former is a well-known bioluminescent substrate, while the latter is a metabolic product of the resulting bioluminescent reaction. While both types of analogs showed anticancer activity toward lung and gastric cancer cell lines, we have obtained data that highlight relevant differences between the activity of these two types of compounds. More specifically, we observed relevant differences in structure–activity relationships between these types of compounds. Also, coelenteramine analogs showed time-dependent activity, while coelenterazine-based compounds usually present time-independent activity. Coelenterazine analogs also appear to be relatively safer toward noncancer cells than coelenteramine analogs. There was also seen a correlation between the activity of the coelenterazine-based compounds and their light-emission properties. Thus, these results further indicate the potential of the marine coelenterazine chemi-/bioluminescent system as a source of new molecules with anticancer activity, while providing more insight into their modes of action. [ABSTRACT FROM AUTHOR]

[Display omitted] • The present manuscript focuses on various undergoing clinical trials of PI3K inhibitors for breast cancer treatment. • Structure activity relationship (SAR) study and research conducted for development of effective PI3K inhibitors. • Triazines, quinazoline, quinoline and pyridoxine have explored as PI3K inhibitors. • Manuscript focuses on various granted patent related to PI3K inhibitor. Cancer stands as one of the deadliest diseases, ranking second in terms of its global impact. Despite the presence of numerous compelling theories concerning its origins, none have succeeded in fully elucidating the intricate nature of this ailment. Among the prevailing concerns in today's world, breast cancer proliferation remains a significant issue, particularly affecting females. The abnormal proliferation of the PI3K pathway emerges as a prominent driver of breast cancer, underscoring its role in cellular survival and proliferation. Consequently, targeting this pathway has emerged as a leading strategy in breast cancer therapeutics. Within this context, the present article explores the current landscape of anti-tumour drug development, focusing on structural activity relationships (SAR) in PI3K targeting breast cancer treatment. Notably, certain moieties like triazines, pyrimidine, quinazoline, quinoline, and pyridoxine have been explored as potential PI3K inhibitors for combating breast cancer. Various heterocyclic small molecules are undergoing clinical trials, such as Alpelisib, the first orally available FDA-approved drug targeting PI3K; others include buparlisib, pictilisib, and taselisib, which inhibit class I PI3K. These drugs are used for the treatment of breast cancer but still have various side effects with their high cost. Therefore, the primary goal of this review is to include all current advances in the development of anticancer medicines that target PI3K over-activation in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Hyperuricemia, a disease characterized by elevation of serum uric acid level beyond 6 mg/dL. This elevation led to appearance of symptoms from joint pain to gout and from gout to difficulty in mobility of the patient. So, in this review, we have summarized the pathology of hyperuricemia, discovery of target and discovery of first XO inhibitor. At last, this review provides in-sights about the recently discovered as natural XO inhibitors, followed by design, structure activity relationship and biological activity of synthetic compounds as XO inhibitors discovered between 2020 and 2023 years. At last, the pharmacophores generated in this study will guide new researchers to design and modify the structure of novel XO inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] Autophagy is a ubiquitous pathological/physiological antioxidant cellular reaction in eukaryotic cells. Vacuolar protein sorting 34 (Vps34 or PIK3C3), which plays a crucial role in autophagy, has received much attention. As the only Class III phosphatidylinositol-3 kinase in mammals, Vps34 participates in vesicular transport, nutrient signaling and autophagy. Dysfunctionality of Vps34 induces carcinogenesis, and abnormal autophagy mediated by dysfunction of Vps34 is closely related to the pathological progression of various human diseases, which makes Vps34 a novel target for tumor immunotherapy. In this review, we summarize the molecular mechanisms underlying macroautophagy, and further discuss the structure–activity relationship of Vps34 inhibitors that have been reported in the past decade as well as their potential roles in anticancer immunotherapy to better understand the antitumor mechanism underlying the effects of these inhibitors. [ABSTRACT FROM AUTHOR]