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• Sensor PQC showed a "turn on" fluorescent response for glutathione based on its copper complex. • The detection limits of sensor PQC were 0.17 μM to Cu2+ and 0.20 μM to GSH. • Sensor PQC can be used for filter paper strip test. • Sensor PQC has good cell permeability and could be used as an efficient sensor for mapping Cu2+ and GSH in living cells. Given the important role of biothiols in various physiological processes, there is a need to develop novel fluorescent sensors for detecting them. Herein, a novel "on-off-on" fluorescent sensor (E)- N' -((7-(diethylamino)-2-oxo-2 H -chromen-3-yl)methylene)-6-((quinolin-8-yloxy)methyl)picolinohydrazide (PQC) was synthesized and its absorbance and fluorescence properties were characterized. The sensor PQC could form a stable complex and showed a significant fluorescence quenching response to Cu2+ with a quenching efficiency of approximately 100%, and the PQC- Cu2+ complex showed a fluorescence enhancement response to GSH with a higher recovery rate of above 80% in a CH 3 OH/HEPES (9:1 v/v, pH = 7.23) buffer system. Its detection limits were determined to be 0.17 μM for Cu2+ and 0.20 μM for GSH, and the binding stoichiometry of PQC- Cu2+ was determined to be 1: 1 by Job's plot method. Importantly, the sensor PQC can be used for filter paper strip tests and bioimaging in living cells. [ABSTRACT FROM AUTHOR]

Two new compounds namely [Zn(L1)phen] 3 1 and Ni(L1)phen(MeOH) 2 (L1 = 3, 5-dichlorosalicylaldehyde thiosemicarbazone) were synthesized by the slow evaporation method at room temperature. The structure of ligand L1 was determined using 1H NMR and 13C NMR spectra. X-ray single crystal diffraction analysis revealed that compounds 1 – 2 can form 3D supramolecular network structures through π ··· π stacking and hydrogen bonding interactions. The DFT calculation shows that the coordination of ligand and metal is in good agreement with the experimental results. Hirshfeld surface analysis revealed that H...H and Cl...H interactions were the predominant interactions in compounds 1 – 2. Energy framework analysis indicated that dispersion energy played a dominant role in the energy composition of compounds 1 – 2. The inhibitory effects of compounds 1 – 2 against Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA) were tested using the paper disk diffusion method (1 : E. coli: 18 mm, MRSA: 17 mm, 2 : E. coli: 15 mm, MRSA: 16 mm). Ion releasing experiments were conducted to assess the ion release capacity of compounds 1 – 2 (Zn2+, 4 days, 38.33 µg/mL; Ni2+, 4 days, 29.12 µg/mL). Molecular docking demonstrated the interaction modes of compounds 1 – 2 with UDP- N -acetylenolpyruvoylglucosamine reductase (MurB) and dihydrofolate reductase (DHFR) in bacteria, involving hydrophobic, stacking, hydrogen bonding and halogen bonding interactions. The generation of reactive oxygen species (ROS) in bacteria under the presence of compounds 1 – 2 were evaluated using a fluorescent dye known as dichlorodihydrofluorescein diacetate (DCFH-DA). Potential antibacterial mechanisms of compounds 1 – 2 were proposed. [Display omitted] • Two new compounds [Zn(L1)phen] 3 1 and Ni(L1)phen(MeOH) 2 were synthesized under room temperature. • Compounds 1 – 2 were both extended into a 3D supermolecule network structure via π ··· π stacking and hydrogen bonding interactions. • Compounds 1 – 2 were both potential antibacterial bacterial for E. coli and MRSA (1 : E. coli: 18 mm, MRSA: 17 mm, 2 : E. coli: 15 mm, MRSA: 16 mm). • Molecular docking of protein and DNA for compounds 1 – 2 were investigated. • The potential antibacterial mechanism of compounds 1 – 2 was proposed via combining with theoretical calculation and experimental results. Two new compounds namely [Zn(L1)phen] 3 1 and Ni(L1)phen(MeOH) 2 (L1 = 3, 5-dichlorosalicylaldehyde thiosemicarbazone) were synthesized by the slow evaporation method at room temperature. The structure of ligand L1 was determined using 1H NMR and 13C NMR spectra. X-ray single crystal diffraction analysis revealed that compounds 1 – 2 can form 3D supramolecular network structures through π ··· π stacking and hydrogen bonding interactions. The DFT calculation shows that the coordination of ligand and metal is in good agreement with the experimental results. Hirshfeld surface analysis revealed that H...H and Cl...H interactions were the predominant interactions in compounds 1 – 2. Energy framework analysis indicated that dispersion energy played a dominant role in the energy composition of compounds 1 – 2. The inhibitory effects of compounds 1 – 2 against Escherichia coli (E. coli) and Methicillin-resistant Staphylococcus aureus (MRSA) were tested using the paper disk diffusion method (1 : E. coli: 18 mm, MRSA: 17 mm, 2 : E. coli: 15 mm, MRSA: 16 mm). Ion releasing experiments were conducted to assess the ion release capacity of compounds 1 – 2 (Zn2+, 4 days, 38.33 µg/mL; Ni2+, 4 days, 29.12 µg/mL). Molecular docking demonstrated the interaction modes of compounds 1 – 2 with UDP- N -acetylenolpyruvoylglucosamine reductase (MurB) and dihydrofolate reductase (DHFR) in bacteria, involving hydrophobic, stacking, hydrogen bonding and halogen bonding interactions. The generation of reactive oxygen species (ROS) in bacteria under the presence of compounds 1 – 2 were evaluated using a fluorescent dye known as dichlorodihydrofluorescein diacetate (DCFH-DA). Potential antibacterial mechanisms of compounds 1 – 2 were proposed. [ABSTRACT FROM AUTHOR]

[Display omitted] • The bioavailability and utilization of curcumin derivatives have been improved. • Acrylic resin coating can change drug release performance. • Hela cell imaging experiments display excellent cellular permeability. • The polymers have good fluorescence imaging ability in different channels of different cells. Curcumin has a broad-spectrum anti-tumor effect and has no toxic side effects. However, the unique diketone structure of curcumin will undergo diketo-enol tautomerism under different acid-base conditions, resulting in its instability under physiological conditions. In addition, the low biocompatibility and absorption rate of curcumin also limit the use of curcumin drugs. In this paper, curcumin was modified by substitution of acryloyl and acrylsulfonyl groups, and four kinds of nanoparticles with regular morphology were prepared using non-toxic and non-irritating acrylic resin as coating material to improve the stability and bioavailability of the compounds. Zeta potential testing shows that the composites surface carries positive charges and have good stability. In the release experiment, four complexes have the potential for slow and controlled release. Imaging of Hela cells with different channels was performed, and the imaging results showed that the complexes could enter the cells and be absorbed by them, demonstrating good imaging performance. MTT experiments have shown that the complexes have certain anti-tumor activity and low cytotoxicity. In general, the complexes synthesized in this paper have potential in the field of drug fluorescence imaging detection. At the same time, this experiment provides a new idea for the design of slow and controlled release of drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] A novel 131-Iodine labeled and ultrasound-responsive nitric oxide and reactive oxygen species controlled released nanoplatform was successfully constructed as a temporally and spatially control therapeutic strategy for cancer treatment with synergistic Sonodynamic/Nitric oxide/Chemodynamic/Radionuclide therapy. • A novel US-responsive bifunctional molecule (SD) was developed, which could controlled release NO and ROS under US irradiation. • MnO 2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H 2 O 2 to produce.OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. • Toxic ONOO–, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. • 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. • The nanoplatform achieved synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer. Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO 2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO 2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H 2 O 2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO–, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In − vitro and − vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Probe BQM-H2O2 showed a large stokes shift (180 nm) and a low detection limit (LOD = 112.6 nM) • Probe BQM-H2O2 had a high selectivity of the probe for detecting hydrogen peroxide distinguishes it from several other reactive oxygen species. • Probe BQM-H2O2 was successfully applied in the fluorescence imaging of exogenous and endogenous H 2 O 2 in 4T1 cells. • Probe BQM-H2O2 can be successfully used for fluorescence imaging within in Blab/c mice bearing 4T1 graft tumors. Hydrogen peroxide (H 2 O 2), a key reactive oxygen species (ROS), plays crucial roles in redox signaling pathways and immune responses associated with cell proliferation, differentiation, migration, and disease progression. The selective monitoring of overproduced H 2 O 2 is important for understanding the diagnosis and pathogenesis of diseases such as cardiovascular disease, cancers, diabetes, Parkinson's disease, Alzheimer's disease, and inflammation. In this paper, an AIE fluorescent probe BQM-H2O2 was developed by connecting phenyl borate with the fluorophore BQM-PNH for selective detection of H 2 O 2. In the presence of H 2 O 2 at f w = 99% (pH = 7.4, 1% DMSO), the probe BQM-H2O2 could generate strong fluorescent signals due to the oxidation of the borate ester. The probe exhibited high selectivity and a low detection limit toward H 2 O 2 with the calculated LOD of 112.6 nM. Importantly, it was employed in the detection of exogenous and endogenous hydrogen peroxide in 4T1 cells with low cytotoxicity. This probe has also been successfully applied to imaging of H 2 O 2 in Blab/c mice bearing 4T1 graft tumors. [ABSTRACT FROM AUTHOR]

[Display omitted] • SHE-2N provides quick and stably stable labeling of plasma membrane. • No cytotoxicity detected for SHE-2N at concentrations used for imaging. • Suitable for STED nanoscopy and two-photon excitation microscopy. • SHE-2N offers high photostability. • Lipid composition does not affect emission or fluorescence lifetime of SHE-2N. Plasma membranes are vital biological structures, serving as protective barriers and participating in various cellular processes. In the field of super-resolution optical microscopy, stimulated emission depletion (STED) nanoscopy has emerged as a powerful method for investigating plasma membrane-related phenomena. However, many applications of STED microscopy are critically restricted by the limited availability of suitable fluorescent probes. This paper reports on the development of two amphiphilic membrane probes, SHE-2H and SHE-2 N , specially designed for STED nanoscopy. SHE-2 N , in particular, demonstrates quick and stable plasma membrane labelling with negligible intracellular redistribution. Both probes exhibit outstanding photostability and resolution improvement in STED nanoscopy, and are also suited for two-photon excitation microscopy. Furthermore, microscopy experiments and cytotoxicity tests revealed no noticeable cytotoxicity of probe SHE-2 N at concentration used for fluorescence imaging. Spectral analysis and fluorescence lifetime measurements conducted on probe SHE-2 N using giant unilamellar vesicles, revealed that emission spectra and fluorescence lifetimes exhibited minimal sensitivity to lipid composition variations. These novel probes significantly augment the arsenal of tools available for high-resolution plasma membrane research, enabling a more profound exploration of cellular processes and dynamics. [ABSTRACT FROM AUTHOR]

[Display omitted] • Twenty arylformylhydrazone butylphenyltin complexes were synthesized. • The C2 exhibits high activity and selectivity in inhibiting the HepG2 cell line. • The C2 causes cell apoptosis by the mitochondrial pathway. Many diorganotin complexes with various alkyl groups exhibit excellent in vitro anticancer activity. However, most diorganotin is the same alkyl group, and the asymmetric alkyl R group has been rarely reported. Hence, in this paper, twenty butylphenyl mixed dialkyltin arylformylhydrazone complexes have been synthesized by microwave "one-pot" reaction with arylformylhydrazine, substituted α-keto acid or its sodium salt and butylphenyltin dichloride. The crystal structures of nine complexes were determined, indicating that the complexes C1 , C2 , C11 , C12 , and C16 ∼ C19 possessed a central symmetric structure of a dinuclear Sn 2 O 2 tetrahedral ring; while the complex C9 is a trinuclear tin-oxygen cluster with a 6-membered ring encased in a 12-membered macrocyclic structure. The inhibiting activity of complexes was tested against the human cell lines NCI-H460, MCF-7, HepG2, Huh-7 and HL-7702. Complex C2 demonstrated the optimal inhibitory effect on HepG2 cells, with an IC 50 value of 0.82 ± 0.03 μM. Cellular biology experiments revealed that complex C2 could induce apoptosis and G2/M phase cell cycle arrest in HepG2 and Huh-7 cells. The complex also caused the collapse of the mitochondrial membrane potential and increased intracellular reactive oxygen species in HepG2 and Huh-7 cells. Western blot analysis further clarified that complex C2 could induce cell apoptosis through the mitochondrial pathway along with the release of reactive oxygen species. [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]

Fifteen kinds of unnatural monosaccharides prepared to compare the relationships of structures and S-glyco-modification labeling. Our results demonstrated that Ac 4 GlcNAz and Ac 4 GalNAz exhibited the most remarkable labeling effects among the detected compounds, other modifications lead to minimal side reactions of S-glyco-modification. [Display omitted] • Fifteen unnatural monosaccharides are prepared to compare the relationships of structures and S-glyco-modification labeling. • Subtle modifications of monosaccharide lead to minimal side reactions of S-glyco-modification. The approach of metabolic chemical reporters (MCRs) for labeling proteins has been widely used in the past several decades. Nevertheless, artificial side reaction generated with fully protected MCRs, termed S-glyco-modification, occurs with cysteine residues through base-promoted β-elimination and Michael addition, leading to false positives in the proteomic identification. Therefore, next generation of MCRs, including partially protected strategy and modifications on the backbone of monosaccharides, have emerged to improve the labeling efficiency. In this paper, we prepared fifteen kinds of unnatural monosaccharides to investigate the relationships of structures and S-glyco-modification labeling. Our results demonstrated that Ac 4 GlcNAz and Ac 4 GalNAz exhibited the most remarkable labeling effects among the detected compounds. Of note, Ac 4 ManNAz, Ac 4 6AzGlucose and Ac 4 6AzGalactose containing similar structures but did not show similar robust signals as them. Moreover, other modifications on the 1-, 2-, 3-, 4- and 6-site indicated minimal side reactions of S-glyco-modification, raising a possibility that subtle modifications of monosaccharide substrate may alter its role in the process of biosynthesis, for example, by change of electronegativity or enhancement of steric hindrance effects. In conclusion, our discoveries provide a new avenue to choose appropriate probe for selective label proteins in vitro and in vivo without undesired S-glyco-modification. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series β-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated for promoting pancreatic islet β cell proliferation. • Compounds A1, A4 and B4 could inhibit the expression of DYRK1A by promoting its degradation. • Compounds A1, A4 and B4 could increase the expression of PCNA and Ki67. • Compounds A1, A4 and B4 were predicted to have better pharmacokinetic properties than positive harmine. Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote β cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series β-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet β cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet β cell proliferation at a concentration of 1 μM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that β-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic β cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel pyrido[1,2- a ]pyrimidinone derivatives were identified as potential allosteric SHP2 inhibitors. • 14i displayed high enzymatic activity against full-length SHP2 (IC 50 = 0.104 μM), while showing low inhibitory effect on SHP2-PTP (IC 50 > 50 μM). • 14i exhibited the antiproliferative activity against the Kyse-520 cells with IC 50 value of 1.06 μM, and low toxicity against the human normal cells HBMEC (IC 50 = 30.75 μM). • 14i could induce cell apoptosis, arrest the cell cycle at the G0/G1 phase and downregulate the phosphorylation levels of Akt and Erk1/2 in Kyse-520 cells. SHP2 (Src homology-2-containing protein tyrosine phosphatase 2) plays an important role in cell proliferation, survival, migration by affecting RAS-ERK, PI3K-AKT, JAK-STAT signaling pathways and so on. Overexpression or gene mutation of SHP2 is closely linked with a variety of cancers, making it a potential therapeutic target for cancer disease. In this paper, 30 target compounds bearing pyrido[1,2- a ]pyrimidin-4-one core were synthesized via two-round design strategy by means of scaffold hopping protocol. It was evaluated the in vitro enzymatic inhibition and cell antiproliferation assay of these targets. 13a , designed in the first round, presented relatively good inhibitory activity, but its molecular rigidity might limit further improvement by hindering the formation of the desired "bidentate ligand", as revealed by molecular docking studies. In our second-round design, S atom as a linker was inserted into the core and the 7-aryl group to enhance the flexibility of the structure. The screening result revealed that 14i could exhibit high enzymatic activity against full-length SHP2 (IC 50 = 0.104 μM), while showing low inhibitory effect on SHP2-PTP (IC 50 > 50 μM). 14i also demonstrated high antiproliferative activity against the Kyse-520 cells (IC 50 = 1.06 μM) with low toxicity against the human brain microvascular endothelial cells HBMEC (IC 50 = 30.75 μM). 14i also displayed stronger inhibitory activities on NCI-H358 and MIA-PaCa2 cells compared to that of SHP099. Mechanistic studies revealed that 14i could induce cell apoptosis, arrest the cell cycle at the G0/G1 phase and downregulate the phosphorylation levels of Akt and Erk1/2 in Kyse-520 cells. Molecular docking and molecular dynamics studies displayed more detailed information on the binding mode and binding mechanism of 14i and SHP2. These data suggest that 14i has the potential to be a promising lead compound for our further investigation of SHP2 inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • DNMTs are overexpressed in various cancers and are positively correlated with tumor initiation and progression. • Targeting DNMTs is a promising strategy for cancer treatment. • The advances of DNMT inhibitors as anticancer agents were reviewed. • The chemical structures, mechanisms of action, and clinical applications of DNMT inhibitors are summarized in this paper. DNA methyltransferases (DNMTs) play a crucial role in genomic DNA methylation. In mammals, DNMTs regulate the dynamic patterns of DNA methylation in embryonic and adult cells. Abnormal functions of DNMTs are often indicative of cancers, including overall hypomethylation and partial hypermethylation of tumor suppressor genes (TSG), which accelerate the malignancy of tumors, worsen the condition of patients, and significantly exacerbate the difficulty of cancer treatment. Currently, nucleoside DNMT inhibitors such as Azacytidine and Decitabine have been approved by the FDA and EMA for the treatment of acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelodysplastic syndrome (MDS). Therefore, targeting DNMTs is a very promising anti-tumor strategy. This review mainly summarizes the therapeutic effects of DNMT inhibitors on cancers. It aims to provide more possibilities for the treatment of cancers by discovering more DNMT inhibitors with high activity, high selectivity, and good drug-like properties in the future. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03 , a HIF-1α inhibitor previously reported by our group, and Tazemetostat , an EZH2 inhibitor approved by FDA, as lead compounds. • D-01 displayed obviously inhibitive effect against the migration, clone and the invasion of A549 cells, tube formation of HUVECs, as well as well tolerated characteristic. • D-01 has good pharmacokinetic properties, the in vitro metabolism of DYB-05 remained in rat liver microsomes, with half-lives of 52 min, These characteristics make D-01 have the potential of tumor treatment. We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03 , a HIF-1α inhibitor previously reported by our group, and Tazemetostat , an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds. [ABSTRACT FROM AUTHOR]

A series of new Mobocertinib derivatives are used as EGFR inhibitors for the treatment of NSCLC, with H-13 being the most promising anti-tumor compound. [Display omitted] • Designed and synthesized 63 Mobocertinib derivatives. • The compounds showed moderate to excellent potency in antiproliferative activity. • Compounds H-13 could induce apoptosis of non-small cell lung cancer H1975 cancer cells. • Molecular dynamics simulation further explored the binding mode of compound H-13 and EGFRT790M proteins. Mobocertinib, as a structural analog of the third generation TKI Osimertinib, can selectively act on the EGFRex20 mutation. We have structurally modified Mobocertinib to obtain new EGFR inhibitors. In this paper, we chose Mobocertinib as a lead compound for structural modification to investigate the effect of Mobocertinib derivatives on EGFRT790M mutation. We designed and synthesized 63 Mobocertinib derivatives by structural modification using the structural similarity strategy and the bioelectronic isoarrangement principle. Then, we evaluated the in vitro antitumor activity of the 63 Mobocertinib derivatives and found that the IC 50 of compound H-13 against EGFRL858R/T790M mutated H1975 cells was 3.91 μM, and in further kinase activity evaluation, the IC 50 of H-13 against EGFRL858R/T790M kinase was 395.2 nM. In addition, the preferred compound H-13 was able to promote apoptosis of H1975 tumor cells and block the proliferation of H1975 cells in the G0/G1 phase; meanwhile, it was able to significantly inhibit the migratory ability of H1975 tumor cells and inhibit the growth of H1975 cells in a time-concentration-dependent manner. In the in vivo anti-tumor activity study, the preferred compound H-13 had no obvious toxicity to normal mice, and the tumor inhibition effect on H1975 cell-loaded nude mice was close to that of Mobocertinib. Finally, molecular dynamics simulations showed that the binding energy between compound H-13 and 3IKA protein was calculated to be −162.417 ± 14.559 kJ/mol. In summary, the preferred compound H-13 can be a potential third-generation EGFR inhibitor. [ABSTRACT FROM AUTHOR]

[Display omitted] • Simple, cost effective and good yielded synthesis. • Novel Phenolic Benzothiazole Structures. • High glycosidase inhibition compared with acarbose. α-Glycosidase inhibition is one of the main approaches to treat Diabetes mellitus. Polyphenolic moieties are known to be responsible for yielding exhibit potent α-glycosidase inhibitory effects. In addition, compounds containing benzothiazole and Schiff base functionalities were previously reported to show α-glycosidase inhibition. In this paper, the synthesis of seven new phloroglucinol-containing benzothiazole Schiff base derivatives through the reaction of 6-substituted-2-aminobenzothiazole compounds with 2,4,6-trihydroxybenzaldehyde using acetic acid as a catalyst was reported. The synthesized compounds were characterized using spectroscopic methods such as FT-IR, 1H NMR, 13C NMR, and elemental analysis. The synthesized compounds were evaluated for their inhibitory effects on α-glycosidase, compounds 3f and 3 g were found to show significant inhibitory properties when compared to the positive control. The IC 50 values of 3f and 3 g were calculated as 24.05 ± 2.28 and 18.51 ± 1.19 µM, respectively. Kinetic studies revealed that compounds 3f and 3 g exhibited uncompetitive mode of inhibition against α-glycosidase. Molecular modeling predicted druglikeness for the title compounds and underpinned the importance of phloroglucinol hydroxyls for interacting with the key residues of α-glycosidase. [ABSTRACT FROM AUTHOR]

[Display omitted] • This paper identifies natural inhibitors of Syk from traditional Chinese medicine. • Sophoraflavanone G (SFG) is confirmed as a novel natural Syk inhibitor with an IC 50 of 2.2 μM. • The binding kinetics and stability of SFG and Syk were analyzed by molecular dynamics simulation. • SFG binds to Syk stably and inhibits its downstream signaling pathways in mast cells. • SFG suppresses IgE-mediated mast cell degranulation and allergic response both in vitro and in vivo. Spleen tyrosine kinase (Syk) plays a crucial role as a target for allergy treatment due to its involvement in immunoreceptor signaling. The purpose of this study was to identify natural inhibitors of Syk and assess their effects on the IgE-mediated allergic response in mast cells and ICR mice. A list of eight compounds was selected based on pharmacophore and molecular docking, showing potential inhibitory effects through virtual screening. Among these compounds, sophoraflavanone G (SFG) was found to inhibit Syk activity in an enzymatic assay, with an IC 50 value of 2.2 μM. To investigate the conformational dynamics of the SYK-SFG system, we performed molecular dynamics simulations. The stability of the binding between SFG and Syk was evaluated using root mean square deviation (RMSD) and root mean square fluctuation (RMSF). In RBL-2H3 cells, SFG demonstrated a dose-dependent suppression of IgE/BSA-induced mast cell degranulation, with no significant cytotoxicity observed at concentrations below 10.0 μM within 24 h. Furthermore, SFG reduced the production of TNF-α and IL-4 in RBL-2H3 cells. Mechanistic investigations revealed that SFG inhibited downstream signaling proteins, including phospholipase Cγ1 (PLCγ1), as well as mitogen-activated protein kinases (AKT, Erk1/2, p38, and JNK), in mast cells in a dose-dependent manner. Passive cutaneous anaphylaxis (PCA) experiments demonstrated that SFG could reduce ear swelling, mast cell degranulation, and the expression of COX-2 and IL-4. Overall, our findings identify naturally occurring SFG as a direct inhibitor of Syk that effectively suppresses mast cell degranulation both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of cinnamylaldehyde-derived mono-carbonyl curcumin analogs were designed and synthesized base combination principles. • H1 showed potential anti-gastric cancer activity through suppression of the STAT3 and AKT signaling pathway in vitro and in vivo. • H1 exhibited better anti-gastric cancer activity compared to 5-FU. The structural modification of curcumin has always been a hotspot in drug development. In this paper, a class of cinnamylaldehyde-derived mono-carbonyl curcumin analogs (MCAs) with 7-carbon-links were designed and synthesized and their anticancer properties were evaluated. Through screening anti-gastric cancer activity of these compounds, H1 exhibited the strongest cytotoxic activity by inhibiting cell viability and colony formation, inducing cell cycle G2/M phase arrest in vitro (SGC-7901 and AGS gastric cancer cells). Moreover, the SGC-7901 subcutaneous tumor-bearing mice studies revealed that H1 significantly inhibited the tumor growth of gastric cancer. We explored the possible potential targets of H1 through network pharmacology. Mechanistically, our results demonstrated that H1 showed potential anti-gastric cancer activity through suppression of the STAT3 and AKT signaling pathway in vitro and in vivo , which was validated by molecular docking. Overall, our results indicate the potential of H1 as a potent chemotherapeutic drug against gastric cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • Triazolopyrimidines, isoxazolopyrimidines and pyrrole-based (DSM compounds) Pf DHODH inhibitors emerged as antimalarial agents. • This review paper highlighted all the synthetic approaches used for the synthesis of DSM compounds. • Synthetic schemes along with various catalysts and chemical reagents used for the synthesis of DSM compounds are depicted here. • SAR studies are discussed with the effects of various substitutions at different positions in DSM compounds. • This review highlighted the optimization of DSM compounds with improved potency, selectivity, and metabolic stability. One of the deadliest infectious diseases, malaria, still has a significant impact on global morbidity and mortality. Plasmodium falciparum dihydroorotate dehydrogenase (Pf DHODH) catalyzes the fourth step in de novo pyrimidine nucleotide biosynthesis and has been clinically validated as an innovative and promising target for the development of novel targeted antimalarial drugs. Pf DHODH inhibitors have the potential to significantly slow down parasite growth at the blood and liver stages. Several Pf DHODH inhibitors based on various scaffolds have been explored over the past two decades. Among them, triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based derivatives known as DSM compounds showed tremendous potential as novel antimalarial agents, and one of the triazolopyrimidine-based compounds (DSM265) was able to reach phase IIa clinical trials. DSM compounds were synthesized as Pf DHODH inhibitors with various substitutions based on structure-guided medicinal chemistry approaches and further optimised as well. For the first time, this review provides an overview of all the synthetic approaches used for the synthesis, alternative synthetic routes, and novel strategies involving various catalysts and chemical reagents that have been used to synthesize DSM compounds. We have also summarized SAR study of all these Pf DHODH inhibitors. In an attempt to assist readers, scientists, and researchers involved in the development of new Pf DHODH inhibitors as antimalarials, this review provides accessibility of all synthetic techniques and SAR studies of the most promising triazolopyrimidines, isoxazolopyrimidines, and pyrrole-based Pf DHODH inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • This paper has showed four new drimane-type sesquiterpenoids and two new nucleosides from the Helicoma septoconstrictum. • Helicoside C (compounds 4) mediated intracellular ROS and mitochondrial dependent apoptosis in ovarian cancer A2780 cells. • Helicoside C could suppress the STAT3′s phosphorylation in A2780 cells. Four new drimane-type sesquiterpenoids and two new nucleoside derivatives (1–6), were isolated from the fungus Helicoma septoconstrictum. Their structures were determined based on the combination of the analysis of their HR-ESI-MS, NMR, ECD calculations data and acid hydrolysis. All the isolated compounds were detected for their bio-activities against MDA-MB-231, A549/DDP, A2780 and HepG2 cell lines. Helicoside C (4) exhibited superior cytotoxicity against the A2780 cell line with IC 50 7.5 ± 1.5 µM. The analysis of reactive oxygen species (ROS) revealed that Helicoside C induced an increase in intracellular ROS. Furthermore, the flow cytometry and mitochondrial membrane potential (MMP) analyses unveiled that Helicoside C mediated mitochondrial-dependent apoptosis in A2780 cells. The western blotting test showed that Helicoside C could suppress the STAT3′s phosphorylation. These findings offered crucial support for development of H. septoconstrictum and highlighted the potential application of drimane-type sesquiterpenoids in pharmaceuticals. [ABSTRACT FROM AUTHOR]

In order to study the influence of amino group on antioxidant activity of oligosaccharides, an amino disaccharide, 6,6′-diamino-6,6′-dideoxytrehalose (DAMDT) was successfully prepared in this paper, and its antioxidant activities against DPPH, superoxide, hydrogen peroxide, and hydroxyl radicals, and reducing power were evaluated, respectively. The results indicated that DAMDT had better antioxidant activity than trehalose at any tested concentration. The influence of amino group on antioxidant activity of disaccharides is positive based on the results in this paper, and amination should be an effective method to improve the bioactivity of saccharides. [ABSTRACT FROM AUTHOR]

[Display omitted] • Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3- d ]pyrimidines. • Computer-aided drug design (CADD) approaches for combat COVID-19. • Novel non-covalent inhibitors of the active site and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro. • Potential COVID-19 drug candidates. • Molecular docking and in silico ADMET studies. • Molecular docking (protein‒ligand) studies on the human body temperature-dependent MPro protein contain zincII (ZnII) ion between His41/Cys145 catalytic dyad in the active site. In this paper, an environmentally benign, convenient, and efficient one-pot three-component reaction has been developed for the regioselective synthesis of novel 5-aroyl(or heteroaroyl)-6-(alkylamino)-1,3-dimethylfuro[2,3- d ]pyrimidine-2,4(1 H ,3 H)-diones (4a‒n) through the sequential condensation of aryl(or heteroaryl)glyoxal monohydrates (1a‒g), 1,3-dimethylbarbituric acid (2), and alkyl(viz. cyclohexyl or tert -butyl)isocyanides (3a or 3b) catalyzed by ultra-low loading ZrOCl 2 •8H 2 O (just 2 mol%) in water at 50 ˚C. After synthesis and characterization of the mentioned furo[2,3- d ]pyrimidines (4a‒n), their multi-targeting inhibitory properties were investigated against the active site and putative allosteric hotspots of both SARS-CoV-2 main protease (MPro) and papain-like protease (PLPro) based on molecular docking studies and compare the attained results with various medicinal compounds which approximately in three past years were used, introduced, and or repurposed to fight against COVID-19. Furthermore, drug-likeness properties of the mentioned small heterocyclic frameworks (4a‒n) have been explored using in silico ADMET analyses. Interestingly, the molecular docking studies and ADMET-related data revealed that the novel series of furo[2,3- d ]pyrimidines (4a‒n), especially 5-(3,4-methylendioxybenzoyl)-6-(cyclohexylamino)-1,3-dimethylfuro[2,3- d ]pyrimidine-2,4(1 H ,3 H)-dione (4g) as hit one is potential COVID-19 drug candidate, can subject to further in vitro and in vivo studies. It is worthwhile to note that the protein–ligand-type molecular docking studies on the human body temperature-dependent MPro protein that surprisingly contains zincII (ZnII) ion between His41/Cys145 catalytic dyad in the active site, which undoubtedly can make new plans for designing novel SARS-CoV-2 MPro inhibitors, is performed for the first time in this paper, to the best of our knowledge. [ABSTRACT FROM AUTHOR]

[Display omitted] • Tetrapluera tetraptera is an important medicinal plant with numerous health benefits. • It has abundant phytochemicals with antimicrobial and antiinflammatory activities. • Targeted research on plant products can help translate these bioactivities to combat the growing threat of drug resistance. The use of medicinal plants has gained renewed wide popularity in Africa, Asia, and most parts of the world because of the decreasing efficacy of synthetic drugs. Thus, natural products serve as a potent source of alternative remedy. Tetrapleura tetraptera is a medicinal plant with cultural and traditional significance in West Africa. In addition to the plant being commonly used as a spice in the preparation of traditional spicy food for postpartum care it is also widely used to constitute herbal concoctions and decoctions for treatment of diseases. This review aimed to provide an up-to-date information on the ethnomedicinal uses, pharmacological activities and phytoconstituents of T. tetraptera. Preclinical studies regarding the plant's toxicity profile were also reviewed. For this updated review, literature search was done on PubMed, Science Direct, Wiley, and Google Scholar databases using the relevant keywords. The review used a total of 106 papers that met the inclusion criteria from January 1989 - February 2022 and summarised the bioactivities that have been reported for the rich phytoconstituents of T. tetraptera studied using various chemical methods. Considering the huge report, the review focused on the antimicrobial and antiinflammatory activities of the plant extracts and isolated compounds. Aridan, aridanin and several bioactive compounds of T. tetraptera have shown pharmacological activities though their mechanisms of action are yet to be fully understood. This study also highlighted the influence of plant parts and extraction solvents on its biological activities. It also presented data on the toxicological profile of the plant extracts using different models. From cultural uses to modern pharmacological research the bioactive compounds of T. tetraptera have proved effective in infectious disease management. We hope that this paper provided a robust summary of the biological activities and toxicological profile of T. tetraptera , thus calling for more research into the pharmacological and pharmacokinetic activities of natural products to help combat the growing threat of drug resistance and provide guidelines for their ethnomedicinal uses. [ABSTRACT FROM AUTHOR]

[Display omitted] The two subtypes of cannabinoid receptors (CBR), namely CB 1 R and CB 2 R, belong to the G protein-coupled receptor (GPCR) superfamily and are confirmed as potential therapeutic targets for a variety of diseases such as inflammation, neuropathic pain, and immune-related disorders. Since CB 1 R is mainly distributed in the central nervous system (CNS), it could produce severe psychiatric adverse reactions and addiction. In contrast, CB 2 R are predominantly distributed in the peripheral immune system with minimal CNS-related side effects. Therefore, more attention has been devoted to the discovery of CB 2 R ligands. In view of the favorable profile of CB 2 R, many high-binding affinity and selectivity CB 2 R ligands have been developed recently. This paper reviews recent research progress on CB 2 R ligands, including endogenous CB 2 R ligands, natural compounds, and novel small molecules, in order to provide a reference for subsequent CB 2 R ligand development. [ABSTRACT FROM AUTHOR]

[Display omitted] • 18 novel drug molecules of microtubulin and EGFR dual-target were prepared. • 10c showed moderate inhibition of tubulin polymerization and potent inhibition of EGFR kinase. • 10c displayed ideal tumor growth inhibition in the A549 cancer bearing nude mice models. • The balanced dual-target antitumor design could inspire the further development of single-molecule multi-target drugs. Motivated by the clinical success of combining tyrosine kinase inhibitors with microtubule-targeted drugs in antitumor treatment, this paper presents a novel combi-targeting design for dual-target inhibitors, featuring arylformylurea-coupled quinazoline backbones. A series of target compounds (10a-10r) were designed, synthesized, and characterized. Biological assessments demonstrated that 10c notably potentiated ten tumor cell lines in vitro, with IC 50 values ranging from 1.04 µM to 7.66 µM. Importantly, 10c (IC 50 = 10.66 nM) exhibited superior inhibitory activity against EGFR kinases compared to the reference drug Gefitinib (25.42 nM) and reduced phosphorylated levels of EGFR, AKT, and ERK. Moreover, 10c significantly impeded tubulin polymerization, disrupted the intracellular microtubule network in A549 cells, induced apoptosis, led to S-phase cell cycle arrest, and hindered cell migration. In anticancer evaluation tests using A549 cancer-bearing nude mice models, 10c showed a therapeutic effect similar to Gefitinib, but required only half the dosage (15 mg/kg). These findings indicate that compound 10c is a promising dual-target candidate for anticancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • The design and synthesis of new indolinone-tethered benzothiophene hybrids were reported. • First, MICs were determined against the sensitive M. tuberculosis strain ATCC 25177. • The most potent compounds were furtherly assessed versus resistant MDR-TB and XDR-TB. • Validated in vivo pharmacokinetic study was performed for the most potent derivative 6 h. • Molecular docking was carried out in DprE1 active site. Joining the global effort to eradicate tuberculosis, one of the deadliest infectious killers in the world, we disclose in this paper the design and synthesis of new indolinone-tethered benzothiophene hybrids 6a-i and 7a-i as potential anti-tubercular agents. The MICs were determined in vitro for the synthesized compounds against the sensitive M. tuberculosis strain ATCC 25177. Potent compounds 6b , 6d , 6f , 6h , 7a , 7b, 7d , 7f , 7h and 7i were furtherly assessed versus resistant MDR-TB and XDR-TB. Structure activity relationship investigation of the synthesized compounds was illustrated, accordingly. Superlative potency was unveiled for compound 6h (MIC = 0.48, 1.95 and 7.81 µg/mL for ATCC 25177 sensitive TB strain, resistant MDR-TB and XDR-TB, respectively). Moreover, validated in vivo pharmacokinetic study was performed for the most potent derivative 6h revealing superior pharmacokinetic profile over the reference drug. For further exploration of the anti-tubercular mechanism of action, molecular docking was carried out for the former compound in DprE1 active site as one of the important biological targets of TB. The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency. [ABSTRACT FROM AUTHOR]

[Display omitted] • EE2 interacts with both SM and SM/Chol monolayers at the air/water interface. • The morphology and permeability was induced by EE2 only to SM/Chol GUVs. • The L o phase regulate the permeability of the vesicles in presence of EE2. Hormone treatments are frequently associated with cardiovascular diseases and cancers in women. Additionally, the detrimental effects of their presence as contaminants in water remain a concern. The transport of hormones through cell membranes is essential for their biological action, but investigating cell permeability is challenging owing to the experimental difficulty in dealing with whole cells. In this paper, we study the interaction of the synthetic hormone 17α-ethynylestradiol (EE2) with membrane models containing the key raft components sphingomyelin (SM) and cholesterol (Chol). The models consisted of Langmuir monolayers and giant unilamellar vesicles (GUVs) that represent bilayers. EE2 induced expansion of SM monolayers upon interacting with the non-hydrated amide group of SM head, but it had practically no effect on SM GUVs because these group are not available for interaction in bilayers. In contrast, EE2 interacted with hydrated phosphate group ( P O 2 -) and amide group of SM/Chol mixture monolayer, which could explain the loss in phase contrast of liquid-ordered GUVs suggesting pore formation. A comparison with reported EE2 effects on GUVs in the fluid phase, for which no loss in phase contrast was observed, indicates that the liquid-ordered phase consisting of lipid rafts is relevant to be associated with the changes on cell permeability caused by the hormones. [ABSTRACT FROM AUTHOR]

[Display omitted] • The bicyclic α-iminophosphonates showed high synthetic possibilities. • Imidazoline I 2 receptors are promising therapeutic targets in neurodegeneration. • (Octahydropyrrolo[3,4- c ]pyrrol-1-yl)phosphonates show affinity/selectivity for imidazoline I 2 receptors. • This is the first time, we showed cognitive improvement in C. elegans after I 2 -IR ligands treatment. Recent studies pointed out the modulation of imidazoline I 2 receptors (I 2 -IR) by selective ligands as a putative strategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I 2 -IR ligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I 2 -IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the synthetic possibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedented molecules that showed promising activities as I 2 -IR ligands in human brain tissues and good BBB permeation capabilities. After in silico ADME prediction studies, we assessed the neuroprotective properties of selected compounds and beneficial effect in an in vitro model of Alzheimeŕs and Parkinson's disease. Along with their neuroprotective effect, compounds showed a potent anti-inflammatory response when evaluated in a neuroinflammation cellular model. Moreover, this is the first time that the neuroprotective effects of imidazoline I 2 -IR ligands in a transgenic Alzheimer's disease Caenorhabditis elegans strain are investigated. Using a thrashing assay, we found a significant cognition improvement in this in vivo model after treatment with the new bicyclic α-phosphoprolines. Therefore, our results confirmed the need of exploring structurally new I 2 -IR ligands and their potential for therapeutic strategies in neurodegeneration. [ABSTRACT FROM AUTHOR]

[Display omitted] • A new series of cinnamic acid derivatives were synthesized as anti-virulence agents against Xoo. • Treatment of Xoo with title compounds led to attenuated HR without affecting bacterial growth or survival. • Expression of the Xoo T3SS was suppressed by treatment with title compounds. • The title compounds showed the potential as an alternative inhibitor to traditional bactericides. Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) has a significant impact on rice yield and quality worldwide. Traditionally, bactericide application has been commonly used to control this devastating disease. However, the overuse of fungicides has led to a number of problems such as the development of resistance and environmental pollution. Therefore, the development of new methods and approaches for disease control are still urgent. In this paper, a series of cinnamic acid derivatives were designed and synthesized, and three novel T3SS inhibitors A10, A12 and A20 were discovered. Novel T3SS inhibitors A10, A12 and A20 significantly inhibited the hpa1 promoter activity without affecting Xoo growth. Further studies revealed that the title compounds A10, A12 and A20 significantly impaired hypersensitivity in non-host plant tobacco leaves, while applications on rice significantly reduced symptoms of bacterial leaf blight. RT-PCR showed that compound A20 inhibited the expression of T3SS-related genes. In summary, this work exemplifies the potential of the title compound as an inhibitor of T3SS and its efficacy in the control of bacterial leaf blight. [ABSTRACT FROM AUTHOR]

[Display omitted] • ADAM10. • combinatorial chemistry. • FRET substrates. • chromogenic substrates. • diabetes. Diabetes mellitus (DM) is a disease of civilization. If left untreated, it can cause serious complications and significantly shortens the life time. DM is one of the leading causes of end-stage renal disease (uremia) worldwide. Early diagnosis is a prerequisite for successful treatment, preferably before the first symptoms appear. In this paper, we describe the optimization and synthesis of the internally quenched fluorescent substrate disintegrin and metalloproteinase 10 (ADAM10). Using combinatorial chemistry methods with iterative deconvolution, the substrate specificity of the enzyme in non-primed and primed positions was determined. We used the ABZ-Lys-Ile-Ile-Asn-Leu-Lys-Arg-Tyr(3-NO 2)–NH 2 peptide to study ADAM10 activity in urine samples collected from patients diagnosed with type 2 diabetes, compared to urine samples from healthy volunteers. The proteolytically active enzyme was present in diabetes samples, while in the case of healthy people we did not observe any activity. In conclusion, our study provides a possible basis for further research into the potential role of ADAM10 in the diagnosis of type 2 diabetes. [ABSTRACT FROM AUTHOR]

[Display omitted] • New brominated TPT3 derivatives were designed and synthesized. • The brominated TPT3 bases can decrease the mispairing with natural bases. • The in vitro replication fidelity of d2-bromo-TPT3-dNaM is shown to be higher than d TPT3-dNaM for the first time. • The in vivo replication fidelity of d2-bromo-TPT3-dNaM is shown close to TPT3-dNaM in the specific sequence context, but a higher in the random sequence context. The high fidelity poses a central role in developing unnatural base pairs (UBPs), which means the high pairing capacity of unnatural bases with their partners, and low mispairing with all the natural bases. Different strategies have been used to develop higher-fidelity UBPs, including optimizing hydrophobic interaction forces between UBPs. Variant substituent groups are allowed to fine tune the hydrophobic forces of different UBPs' candidates. However, the modifications on the skeleton of TPT3 base are rare and the replication fidelity of TPT3-NaM remains hardly to improve so far. In this paper, we reasoned that modifying and/or expanding the aromatic surface by Bromo-substituents to slightly increase hydrophobicity of TPT3 might offer a way to increase the fidelity of this pair. Based on the hypothesis, we synthesized the bromine substituted TPT3, 2-bromo-TPT3 and 2, 4-dibromo-TPT3 as the new TPT3 analogs. While the enzyme reaction kinetic experiments showed that d2-bromo-TPT3-dNaM pair and d2, 4-dibromo-TPT3TP-dNaM pair had slightly less efficient incorporation and extension rates than that of dTPT3-dNaM pair, the assays did reveal that the mispairing of 2-bromo-TPT3 and 2, 4-dibromo-TPT3 with all the natural bases could dramatically decrease in contrast to TPT3. Their lower mispairing capacity promoted us to run polymerase chain amplification reactions, and a higher fidelity of d2-bromo-TPT3-dNaM pair could be obtained with 99.72 ± 0.01% of the in vitro replication fidelity than that of dTPT3-dNaM pair, 99.52 ± 0.09%. In addition, d2-bromo-TPT3-dNaM can also be effectively copied in E. coli cells, which showed the same replication fidelity as that of dTPT3-dNaM in the specific sequence, but a higher fidelity in the random sequence context. [ABSTRACT FROM AUTHOR]

A series of novel bromophenol derivatives were synthesized and evaluated for their antioxidant activity, α-glycosidase and acetylcholinesterase enzymes inhibition properties. The most powerful inhibition was observed from (2,3-Dibromo-4-hydroxy-5-methoxyphenyl)(2,5-dibromo-4-methoxyphenyl)methanone as 4.31 ± 1.93 nM α-glycosidase enzyme, which promise as antidiabetic agent. This compound can be researched in further studies related diabetes mellitus as lead compound. • A series of novel bromophenol derivatives were synthesized. • Their acetylcholinesterase and α-glycosidase inhibition effects was investigated. • DPPH and ABTS⋅+ scavenging effects of bromophenol were evaluated. • Fe3+ and Cu2+ reducing and Fe2+ chelating of bromophenols were determined. • Antioxidant and enzyme inhibition effects of bromophenols were compared to the standards. In this paper, a series of novel bromophenol derivatives were synthesized and evaluated for their acetylcholinesterase and α-glycosidase enzymes inhibition properties and antioxidant activity. Diarylmethanones were synthesized and their bromination was carried out. During bromination, some compounds gave new bromophenols via regioselective O-demethylation. Demethylation of brominated diarylmethanones was also performed with BBr 3 to give novel bromophenols. In addition, we examines the antioxidant capacity of novel bromophenol derivatives using several in vitro bioanalytical methodologies such as 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS⋅+) and 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) radical scavenging activity, Fe3+ and Cu2+ reducing activities and ferrous (Fe2+) ions chelating activities. Also, novel bromophenols and methoxylated bromophenols derivatives were tested against acetylcholinesterase and α-glycosidase, which associated with some metabolic diseases. The novel bromophenols showed Ki values in range of 8.94 ± 0.73–59.45 ± 14.97 nM against AChE and 4.31 ± 1.93–44.14 ± 2.19 nM against α-glycosidase. [ABSTRACT FROM AUTHOR]

• Synthesized a series of novel 3-phosphate derivatives of betulin. • Evaluated antiproliferative in vitro activity against five human cell lines. • Performed molecular docking to six potential anticancer targets. Betulin derivatives exhibit an antiproliferative activity and have been tested for many cancer cell lines. This paper describes a new series of 3-phosphate derivatives of betulin bearing different substituents at C28 position. The synthesized compounds were tested in vitro for their antiproliferative effect against human leukemia (MV-4-11 and CCRF/CEM), lung carcinoma (A549), prostate cancer (DU 145), melanoma (Hs 294T) cell lines, and murine leukemia P388. To explore the possible mechanism of anticancer activity for the most in vitro active compounds (4 , 5 , 7 and 8) and betulin, molecular docking was performed to the binding sites of potential anticancer targets, described for the various triterpene derivatives, including topoisomerase I and II, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR), transcription factor NF-κB, anti-apoptotic protein Bcl-2 and peroxisome proliferator-activated receptor (PPAR γ). According to the results of the docking, the best fit to the binding pocket of PPAR γ was shown by compound 4. [ABSTRACT FROM AUTHOR]

• Characterization, quantitation and evaluation of cardiac glycosides were reported. • The inhibition of Na+,K+-ATPase activity was measured. • Enzyme kinetics and molecular docking were determined. Streblus asper Lour. (Moraceae) is a medicinal plant in Asian countries including India and Thailand, possessing activities of anti-tumor, anti-allergy, anti-parasitic and anti-bacterial. In this paper, characterization, quantitation and similarity evaluation of cardiac glycosides in different parts of S. asper were investigated by HPLC-Q-TOF-MS and chemometric methods. Then, the inhibition of Na+,K+-ATPase activity by the compounds isolated from S. asper was measured. Meanwhile, enzyme kinetics and molecular docking were determined to exhibit the combination modes between cardiac glycosides and Na+,K+-ATPase. As a result, twenty peaks of cardiac glycosides were assigned. Strophanthidin-3- O - α - l -rhamnopyranosyl-(1 → 4)-6-deoxy- β - d -allopyranoside (1), glucostrebloside (2), strebloside (4) and mansonin (8) with a significant activity of inhibiting Na+,K+-ATPase (IC 50 7.55–13.60 μM) were chosen for the determination of enzyme kinetics, exhibiting anticompetitive inhibitory characteristics towards Na+,K+-ATPase. Compound 4 could reasonably bind to the active sites of Na+,K+-ATPase, proved by molecular docking. Furthermore, the contents of the major compounds in four different parts of S. asper were extremely different, analyzed by chemometric methods, similarity analysis and principle compounds analysis. All these findings indicated that the contents of major compounds in different parts of S. asper were extremely different with a significant activity of inhibiting Na+,K+-ATPase, providing a reference for determination of effective part and administered dosage. The combination modes between cardiac glycosides and Na+,K+-ATPase were also revealed by enzyme kinetics and molecular docking, which provided a basis for further study of pharmacological activity. [ABSTRACT FROM AUTHOR]

Two series of sulfonylpiperazines linked [1,3]dioxolo[4,5- g ]chromenones were synthesized featuring phenyl and chalcone bridge representing flavones or homoisoflavonoids and in vitro antioxidant and anticancer properties were investigated. • [1,3]dioxolo[4,5-g]chromenones were inspected for pharmacological properties. • Presence of EWD and ED substituents displayed varied and promising IC50 data. • OCF 3 and OCH 3 played a crucial role against DPPH, ABTS +, SK-OV-3 and HT-29. • Halogen atom(s) attributed excellent inhibitory potential against HeLa and A-549. • Promising activities warrant further studies for the structural optimization. Two series of sulfonylpiperazines linked [1,3]dioxolo[4,5- g ]chromenones were synthesized featuring phenyl (7a-k) and chalcone (12a-k) bridge representing flavones or homoisoflavonoids core. New molecules are synthesized utilizing aldol condensation to inspect as antioxidants against DPPH and ABTS + and antiproliferative agents toward selected human cancer cell lines. Cytotoxicity of new compounds was confirmed using SRB assay against non-cancer MDCK cell line. The results concluded that both individual structures of 7 and 12 were vital for modulating pharmacological potencies and presence of different electron withdrawing and electron donating functional group(s) on the phenylsulfonyl entity yielded varied biological effects. Substituent h (OCF 3) and j , k (OCH 3) were found to play a crucial role scavenging DPPH and ABTS + as well as inhibiting cancer cell lines SK-OV-3 and HT-29. Moreover, molecules bearing halogen atom(s) such as substituent b-g expressed excellent inhibitory potential against HeLa and A-549 cancerous cell lines. Bioassay data displayed some interesting structure-activity relationships which are discussed in this paper. The results justified that tested derivatives are promising antioxidants and cytotoxic agents and warrant further structural optimization and bioassay studies. Spectroscopic techniques such as FT-IR, 1H NMR, 13C NMR and elemental analysis (CHN) were carried out to confirm the final structures. [ABSTRACT FROM AUTHOR]

• New tamoxifen-based compounds were designed and synthesized. • The new compounds acted as antiproliferative agents and apoptosis inducers. • The tamoxifen-xanthene hybrid 1 turned out to be the most active of the series. • Compound 1 also showed a favorable genotoxic profile. Breast cancer is the most diagnosed type of cancer among women for which an exhaustive cure has not been discovered yet. Nowadays, tamoxifen still represents the gold standard for breast cancer therapy; it acts on both estrogen receptor-positive and estrogen receptor-negative breast cancers. Unfortunately, its toxicity and the related chemoresistance undermine its antitumor potential. In this paper, new tamoxifen-based derivatives with a rigid structural motif in their structure were designed, synthesized, and evaluated to assess their antitumor behavior. All the tested compounds affected estrogen receptor-positive tumor (MCF-7) cell growth, even with different extents, among which, the most active ones proved also to induce mitochondria-mediated apoptosis through activation of PARP cleavage, decrease in Bax/Bcl-2 ratio and increase in Bim gene expression levels. Here we found that the compound 1 , carrying a rigid xanthene core, turned out to be the most promising of the set showing an activity profile comparable to that of tamoxifen. Furthermore, a more favorable genotoxic profile than tamoxifen made compound 1 a promising candidate for further studies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis and characterization series of azo-benzamides and a series of azo-imidazolones. • A facile methods were modified for synthesis of an azo-oxazolone, and azo-benzamides. • In vivo antimicrobial activity on infected wound rats. • Acute oral toxicity by up and down method (OECD 425). • In vitro antimicrobial activity and antioxidant power. Abstract In this research paper, a stepwise chemical reaction was conducted to synthesize and develop of a new potent azo-oxazolone, which was used as prototypical molecule for production of two series of azo-benzimide (5a–j) and azo-imidazolone (6a–j). FT-IR, 1H NMR, 13C NMR and CHN analysis were used for the structural elucidation. The high biological efficiency of newly obtained compounds was confirmed by in vitro antioxidant efficacy and in vitro antimicrobial activity against gram-positive and gram-negative bacteria via disc diffusion and tube dilution techniques. In addition, in vivo anti-microbial activity of some of the synthesized compounds was determined by using burnt rats which infected by Staphylococcus aureus. Tested compounds have shown high anti-microbial activity and wound healing in comparison to ucederm as a control. In vivo acute toxicity was carried out by up and down method for the compounds 4, 5d and 6d. The limited test dose was 2000 mg/kg, while the maximum tolerated dose was 5000 mg/kg which has administered no lethality recorded. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Three new cytosporones dothiorelones K–M were isolated from the fungus Dothiorella sp. • Three compounds displayed potent inhibitory activities against α -glucosidase. • This paper indicated that cytosporones will be useful to as diabetes control agents. Abstract Three new cytosporone derivatives dothiorelones K–M (1 , 2 and 7), together with six known ones (3 – 6 , 8 and 9) were isolated from the mangrove-derived fungus Dothiorella sp. ML002. Their structures were determined by comprehensive 1D, 2D NMR spectroscopic and HR-ESI-MS spectroscopic data. Compounds 1 , 2 and 5 displayed inhibitory activities against α -glucosidase with the IC 50 values of 22.0, 77.9 and 5.4 μg/mL, respectively. Additionally, compounds 1 , 2 , and 5 also exhibited antibacterial activities against Staphylococcus aureus (ATCC 6538) with the same MIC values of 50 μg/mL, respectively. The results indicated that cytosporone derivatives will be useful to as diabetes control agents. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Lysozyme modifications were induced by substituted p -benzoquinones. • TBQ and CBQ were more efficient quinones in modifying lysozyme. • MBQ and FBQ were less efficient in modifying lysozyme. • Quinone reduction potentials correlate well with their reactivity trend toward lysozyme. • More lysozyme modifications were observed at higher pH conditions. Abstract Protein misfolding can facilitate a protein damaging process and makes it susceptible to a series of events such as unfolding, adduct formation, oligomerization, or aggregation. Loss of a protein's native structure may result in its biological malfunction and/or cellular toxicity that could cause associated diseases. Several factors were identified for causing structural changes of a protein, however quinone-induced protein modifications received very little attention whether for amyloidal or non-amyloidal proteins. In this paper, we report our investigation on lysozyme modifications upon treatment with selected benzoquinones (BQs), utilizing fluorescence spectroscopy including anisotropy determination, UV–Vis spectroscopy, and SDS-PAGE. Lysozyme was reacted with substituted BQs in order to examine substituent effects on protein modifications. In addition, we evaluated lysozyme modifications induced by 1,4-benzoquinone in concentration-, pH-, temperature-, and time-dependent studies. Our study shows that all BQs can readily modify lysozyme in a complex manner through adduct formation, oligomerization, polymeric aggregation, and/or fibrilization. Electrochemical properties of selected BQs were monitored using cyclic voltammetry in phosphate buffered aqueous solution, and it was found that quinone reduction potentials correlate well with their reactivity trend toward lysozyme. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The mechanism of rearrangement of curcumol to form orobanone analogues is studied. • Curcumol and four orobanone analogues inhibited HIF-1 transcription under hypoxia. • Compound 6 inhibited hypoxia-induced HIF-1 activity in HeLa cells with the IC 50 = 2.4 μM. Abstract In this paper, the mechanism of orobanone analogues formation via aromatization rearrangement of curcumol was minutely explored. Aromatization of curcumol with acetone under acidic condition was selected as the model reaction. The formation of a stable aromatic system was the driving force for this reaction. Based on the model reaction, other four new orobanone analogues were prepared through curcumol reacting with different carbonyl compounds. The results showed that the stability of carbocation, which was generated from the carbonyl compounds, and the steric hindrance were main factors affecting the aromatization. We also synthesized the analogue of aromaticane B using compound 2. In vitro anti-proliferative activity of some derivatives were tested by MTT assay. Two derivatives showed weak anti-tumor effect on two cancer cell lines (HepG2 and MCF7) under normoxia. Four orobanone analogue 2 , 5 , 6 and 9 significantly inhibited hypoxia-induced HIF-1 luciferase reporter activity in HeLa cells with the IC 50 values of 13.6, 6.6, 2.4 and 18.2 μM, respectively. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A 3D-QSAR model was produced for the FABP4 inhibitors. • A scaffold hopping suggested 3000 potentially active FABP4 inhibitors. • Three synthesized molecules have shown an IC 50 between 3.70 and 5.59 μM. Abstract Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC 50 values between 3.70 and 5.59 μM, with a high level of agreement with the predicted values. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Series of hydroxylated 2-phenylbenzofuran were synthesized. • Compounds displayed activity against butyrylcholinesterase enzyme. • Importance of number and position of hydroxyl substitution in enzyme activity. • Physicochemical properties of derivatives were characterized. • Docking studies assisted in explaining the structure-activity. Abstract We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthetic analogs of barretin are powerful antioxidants. • Compound prepared display comparable activities as commercial antioxidants. • Changing the hetereocyclic core alters the antioxidative properties. • Simplified analogs of marine natural products display improved bioactivity. Abstract The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low µg/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 µg/mL. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Small organic molecules were found to be effective inhibitors of BACE-1 enzyme. • Tetrahydrobenzo[ b ]pyrans were targeted for the BACE-1 enzyme in docking studies. • Those compounds were synthesized in the lab and characterized using spectral data. • The synthesized compounds were subjected for in-vitro studies against the enzyme. • One compound with code KVB-5 (4e) was showing IC50 value at nanomolar concentration. Abstract β -Secretase (BACE1) has been broadly documented as one of the possible therapeutic targets for the treatment of Alzheimer's disease. In this paper, we report the synthesis and the for β -secretase (BACE-1) inhibitory activity of new series of tetrahydrobenzo [ b ] pyran derivatives. One-pot synthesis of tetrahydrobenzo [ b ] pyrans was carried out by condensing aromatic aldehyde, malononitrile and 1,3-cyclohexanedione using ionic liquid 1-butyl-3-methyl imidazolium chloride ([bmIm]Cl−) in aqueous alcohol media. The addition of alcohol and water in the ratio of 1:2 keeps all the reactants in solution which facilitates the reaction and makes the product formation very easy. The synthesized compounds were subjected to BACE1 inhibition assay and six compounds, 4d, 4e, 4f, 4h, 4i, and 4p have shown significant IC 50 values at micromolar level. Among these six active compounds, 4e was a potential inhibitor with its IC 50 value in nanomolar range. All the synthesized compounds were docked onto the active site of β -Secretase enzyme. [ABSTRACT FROM AUTHOR]

Graphical abstract New pyrazoles and pyrazolo pyridines were synthesized and their structure was confirmed by elemental analyses as well as IR, 1H NMR, 13C NMR, and mass spectral data. All the newly synthesized derivatives were evaluated in vitro for inhibitory activity against COX-1 and COX-2 enzymes and their IC 50 values were calculated, most of the derivatives showed good inhibitory activity with derivatives IVb, IVh and IVJ showing inhibitory activity better than celecoxib. Moreover, the eight most potent derivatives IVa, IVb, IVc, IVd, IVe, IVh, IVJ, and IVL were selected for in vivo assay to measure their effect on paw edema in rates and their ulcerogenic effect. Compounds IVa, IVb and IVc were found to be the most active and selective as COX-2 inhibitors and most effective in protection from edema they also have lowest ulcerogenic effect among all derivatives. Highlights • This paper describes the synthesis of new pyrazoles and pyrozolo [3,4- b ] pyridines. • The new derivatives were evaluated for COX-1, COX-2 inhibitory activities and anti-inflammatory activity. • Their safety was examined by their ulcerogenic effect. • Some derivatives showed potent activity compared to celecoxib and indomethacin. Abstract New pyrazoles and pyrazolo[3,4- b ] pyridines were synthesized and their structure was confirmed by elemental analyses as well as IR, 1H NMR, 13C NMR, and mass spectral data. All the newly synthesized derivatives were evaluated in vitro for inhibitory activity against COX-1 and COX-2 enzymes and their IC 50 values were calculated, most of the derivatives showed good inhibitory activity with derivatives IVb, IVh and IVJ showing inhibitory activity better than celecoxib. Moreover, the eight most potent derivatives IVa, IVb, IVc, IVd, IVe, IVh, IVJ, and IVL were selected for in vivo assay to measure their effect on paw edema in rates and their ulcerogenic effect. Compounds IVa, IVb and IVc were found to be the most active and selective as COX-2 inhibitors and most effective in protection from edema, they were also found to have lowest ulcerogenic effect among all derivatives. [ABSTRACT FROM AUTHOR]

Graphical abstract A series of oxadiazole-based S1P 1 direct-acting agonists, with high affinity for S1P 1 receptor and favorable selectivity against S1P 3 receptor was designed, synthesized and evaluated in vitro and vivo. Highlights • Oxadiazole-based derivatives were designed and progressively modified as S1P 1 agonists. • The agonism activities of compounds for S1P 1 and S1P 3 receptor were evaluated. • Most compounds show excellent activity and selectivity, particularly for 16-3b and 16 - 3g. • In vivo pharmacological, pharmacokinetics and druggability profiles were studied. • The binding mode between 16-3b and the activated S1P 1 model was also reviewed. Abstract Agonism of S1P 1 receptor has been proven to be responsible for peripheral blood lymphopenia and elicts the identification of various S1P 1 modulators. In this paper we described a series of oxadiazole-based S1P 1 direct-acting agonists disubstituted on terminal benzene ring, with high potency for S1P 1 receptor and favorable selectivity against S1P 3 receptor. In addition, two representative agents named 16-3b and 16 - 3g demonstrated impressive efficacy in lymphocyte reduction along with reduced effect on heart rate when orally administered. Furthermore, these compounds have been shown to possess desired pharmacokinetic (PK) and physicochemical profiles. The binding mode between 16 - 3b and the activated S1P 1 model was also studied. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Successful synthesis of a series of carbamate derivatives of 7-deacetyl-10-thiocolchicine as anticancer agents. • Screening of the synthesized compounds against cancer cell lines: A549, MCF-7, LoVo, LoVo/DX and normal BALB/3T3 cells. • Synthesized several novel thiocolchicines for SAR. • Compounds 7 and 14 identified as the most active with high selectivity. • Mode of action demonstrated in silico to involve the colchicine binding site. Abstract A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4 – 14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4 – 8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC 50 values = 0.009–0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization. [ABSTRACT FROM AUTHOR]