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In this study, new hybrids of quinazolinone-1,2,3-triazole-acetamide were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results obtained from the in vitroscreening indicated that all analogs exhibited significant inhibitory activity against α-glucosidase (IC50values ranging from 4.8–140.2 μM) in comparison to acarbose (IC50= 750.0 μM). The limited structure–activity relationships suggested the variation in the inhibitory activities of the compounds affected by different substitutions on the aryl moiety. The enzyme kinetic studies of the most potent compound 9c, revealed that it inhibited α-glucosidase in a competitive mode with a Kivalue of 4.8 μM. In addition, molecular docking studies investigated the structural perturbation and behavior of all derivatives inside the α-glucosidase active site. Next, molecular dynamic simulations of the most potent compound 9c, were performed to study the behavior of the 9c-complex during the time. The results showed that these compounds can be considered as potential antidiabetic agents.

CK2 is a ubiquitous protein kinase with an anti-apoptotic role and is found to be overexpressed in multiple cancer types. To this end, the inhibition of CK2 is of great interest with regard to the development of novel anti-cancer therapeutics. ATP-site inhibition of CK2 is possible; however, this typically results in poor selectivity due to the highly conserved nature of the catalytic site amongst kinases. An alternative methodology for the modulation of CK2 activity is through allosteric inhibition. The recently identified αD site represents a promising binding site for allosteric inhibition of CK2α. The work presented herein describes the development of a series of CK2α allosteric inhibitors through iterative cycles of X-ray crystallography and enzymatic assays, in addition to both fragment growing and fragment merging design strategies. The lead fragment developed, fragment 8, exhibits a high ligand efficiency, displays no drop off in activity between enzymatic and cellular assays, and successfully engages CK2α in cells. Furthermore, X-ray crystallographic analysis provided indications towards a novel mechanism of allosteric inhibition through αD site binding. Fragments described in this paper therefore represent promising starting points for the development of highly selective allosteric CK2 inhibitors.

In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRASG12Ctend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.

With the development of society and the improvement of people's living standards, there is an increasing demand for melanin-inhibiting products that prioritize health, safety, and efficacy. Therefore, the development of natural products that can safely and efficiently inhibit melanin synthesis is of great social significance and has significant market potential. In this paper, by reviewing the literature reported in recent years, we summarized the natural products with inhibition of melanin synthesis effects that have been put into or not yet put into the market, and classified them according to the chemical groups of their compounds or the extraction methods of the natural products. Through the summary analysis, we found that these compounds mainly include terpenoids, phenylpropanoids, flavonoids and so on, while the natural product extracts mainly include methanol extracts, ethanol extracts, and aqueous extracts. Their main inhibition of melanin synthesis mechanisms include: (1) direct inhibition of tyrosinase activity; (2) down-regulation of the α-MSH-MC1R, Wnt, NO, PI3K/Akt and MAPK pathways through the expression of MITF and its downstream genes TYR, TRP-1, and TRP-2; (3) antioxidant; (4) inhibition of melanocyte growth through cytotoxicity; (5) inhibition of melanosome production and transport. This paper provides an in-depth discussion on the research progress of whitening natural products and their market value. The aim is to offer guidance for future research and development of natural skin whitening products.

Many known chemotherapeutic anticancer agents exhibit neutropenia as a dose-limiting side effect. In this paper we suggest a prodrug concept solving this problem for camptothecin (HO-cpt). The prodrug is programmed according to Boolean “AND” logic. In the absence of H2O2(trigger T1), e.g.in the majority of normal cells, it exists as an inactive oligomer. In cancer cells and in primed neutrophils (high H2O2), the oligomer is disrupted forming intermediate (inactive) lipophilic cationic species. These are accumulated in mitochondria (Mit) of cancer cells, where they are activated by hydrolysis at mitochondrial pH 8 (trigger T2) with formation of camptothecin. In contrast, the intermediates remain stable in neutrophils lacking Mit and therefore a source of T2. In this paper we demonstrated a proof-of-concept. Our prodrug exhibits antitumor activity both in vitroand in vivo, but is not toxic to normal cell and neutrophils in contrast to known single trigger prodrugs and the parent drug HO-cpt.

PD-L1 is a transmembrane protein overexpressed by tumor cells. It binds to PD-1 on the surface of T-cells, suppresses T-cell activity and hinders the immune response against cancer. Clinically, several monoclonal antibodies targeting PD-1/PD-L1 have achieved significant success in cancer immunotherapy. Nevertheless, their disadvantages, such as unchecked immune responses, high cost and long half-life, stimulated pharmacologists to develop small-molecule inhibitors targeting PD-1/PD-L1. After a batch of excellent inhibitors with a biphenyl core structure were firstly reported by BMS, more and more researchers focused on small-molecule inhibitors targeting PD-L1 rather than PD-1. Numerous small-molecule inhibitors were extensively designed and synthesized in the past few years. In this paper, the structural characteristics of PD-L1 and complexes of PD-L1 with its inhibitors are elaborated and small molecule inhibitors developed in the last decade are summarized as well. This paper aims to provide insights into further designing and synthesis of small molecule inhibitors targeting PD-L1.

A practical synthetic route, consisting of 5 steps, has been developed and applied successfully for converting limonin/deoxylimonin into the corresponding amino derivatives I-5a–I-5eand II-5a–II-5e. Deoxylimonin analogs II-5aand II-5bbearing an open A ring structure underwent ring closure reaction by employing the Mitsunobu procedure to afford II-6aand II-6b. All of the 12 newly synthesized compounds were subjected to preliminary screening for evaluating their inflammation and nociception inhibition efficacy. The most promising compounds, I-5band II-5d, were selected for further investigation by a carrageenan-induced mouse paw edema model, both of which displayed a dose–response dependent manner and demonstrated superior anti inflammation capacity to that of indomethacin in the first 2 hours.

Hyperuricemia is characterized by higher-than-normal levels of uric acid in the bloodstream. This condition can increase the likelihood of developing gout, a form of arthritis triggered by the deposition of urate crystals in the joints, leading to inflammation and pain. An essential part of purine metabolism is played by the enzyme xanthine oxidase (XO), which transforms xanthine and hypoxanthine into uric acid. Despite its vital role, diseases such as gout have been associated with elevated uric acid levels, which are linked to increased XO activity. To manage hyperuricemia, this study focuses on potential nitrogen based heterocyclic compounds that may serve as XO inhibitors which may lower uric acid levels and prevent hyperuricemia. Xanthine oxidase inhibitors are a class of medications used to treat conditions like gout by reducing the production of uric acid. The present study demonstrates numerous compounds, particularly nitrogen containing heterocyclic compounds including their synthesis, structure–activity relationship, and molecular docking studies. This paper also contains drugs undergoing clinical studies and the xanthine oxidase inhibitors that have been approved by the FDA.

In a recent paper in this journal (RSC Med. Chem., 2023, 14, 2429), we described an unusually strong impact of regiospecific exchange of phenylalanines by tyrosines in 10 gallium-68-labeled trimers of certain cyclic RGD peptides, c[XRGDLAXp(NMe)K] (X = F or Y), on non-specific organ uptakes. We found that there was, in part, no correlation of liver uptake with established polarity proxies, such as the octanol–water distribution coefficient (log D). Since this observation could not be explained straightforwardly, we suggested that the symmetry of the compounds had resulted in a synergistic interaction of certain components of the macromolecules. In the present work, we investigated whether a comparable effect also occurred for a series of 5 tetramers labeled with lutetium-177. We found that in contrast to the trimers, liver uptake of the tetramers was well correlated to their polarity, indicating that the unusual observations along the trimer series indeed was a unique feature, probably related to their particular symmetry. Since the Lu-177 labeled tetramers are also potential agents for treatment of a variety of αvβ6-integrin expressing cancers, these were evaluated in mice bearing human lung adenocarcinoma xenografts. Due to their tumor-specific uptake and retention in biodistribution and SPECT imaging experiments, these compounds are considered a step forward on the way to αvβ6-integrin-targeted anticancer agents. Furthermore, we noticed that the presence of tyrosines in general had a positive impact on the in vivoperformance of our peptide multimers. In view of the fact that a corresponding rule was already proposed in the context of protein engineering, we argue in favor of considering peptide multimers as a special class of small or medium-sized proteins. In summary, we contend that the performance of peptide multimers is less determined by the in vitrocharacteristics (particularly, affinity and selectivity) of monomers, but rather by the peptides' suitability for the overall macromolecular design concept, and peptides containing tyrosines are preferred.

Decades ago, the application of cyclic sulfonamide (sultam) and its derivatives primarily focused on their antibacterial properties. However, recent years have seen a shift in research attention towards exploring their potential as anticancer, anti-inflammatory, antidiabetic, and antiviral agents. Despite this broadening scope, only a few sultam drugs have made it to the commercial market, as much of the research on sultams remains in the discovery phase. This class of compounds holds significant promise and remains pertinent in pharmaceutical research. Due to sultam's relevance and growing importance in drug discovery, this review paper aims to consolidate and examine the biological activities of sultam derivatives ranging from 4 to 8-membered ring structures.

The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivopharmacokinetic studies were performed to determine the oral exposure of compound 26. Finally, molecular docking elucidated that compound 26could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26represented a promising lead compound for future necroptosis inhibitor development.

The high efficiency and specificity of enzymes make them play an important role in life activities, but the high cost, low stability and high sensitivity of natural enzymes severely restrict their application. In recent years, nanozymes have become convincing alternatives to natural enzymes, finding utility across diverse domains, including biosensing, antibacterial interventions, cancer treatment, and environmental preservation. Nanozymes are characterized by their remarkable attributes, encompassing high stability, cost-effectiveness and robust catalytic activity. Within the contemporary scientific landscape, metal–organic frameworks (MOFs) have garnered considerable attention, primarily due to their versatile applications, spanning catalysis. Notably, MOFs serve as scaffolds for the development of nanozymes, particularly in the context of bacterial detection and treatment. This paper presents a comprehensive review of recent literature pertaining to MOFs and their pivotal role in bacterial detection and treatment. We explored the limitations and prospects for the development of MOF-based nanozymes as a platform for bacterial detection and therapy, and anticipate their great potential and broader clinical applications in addressing medical challenges.

The discovery of novel and highly effective P-gp inhibitors is considered to be an effective strategy for overcoming tumor drug resistance. In this paper, a phenotypic screening viaa self-constructed synthetic methodology-based library identified a new class of tricyclic spiroindole derivatives with excellent tumor multidrug resistance reversal activity. A stereospecific compound OY-103-Bwith the best reversal activity was obtained based on a detailed structure–activity relationship study, metabolic stability optimization and chiral resolution. For the VCR-resistant Eca109 cell line (Eca109/VCR), co-administration of 5.0 μM OY-103-Bresulted in a reversal fold of up to 727.2, superior to the typical third-generation P-gp inhibitor tariquidar. Moreover, the compound inhibited the proliferation of Eca109/VCR cells in a concentration-dependent manner in plate cloning and flow cytometry. Furthermore, fluorescence substrate accumulation assay and chemotherapeutic drug reversal activity tests demonstrated that OY-103-Breversed tumor drug resistance viaP-gp inhibition. In conclusion, this study provides a novel skeleton that inspires the design of new P-gp inhibitors, laying the foundation for the treatment of drug-resistant tumors.

In this paper, we present the design and synthesis of a novel series of pyrido[2,3-d]pyridazine-2,8-dione derivatives viathe annulation of the 2-pyridone pattern. The synthesized derivatives were evaluated for in vivoanti-inflammatory activity using an ear edema model. Compound 7c, which showed a greater inhibition of ear edema (82%), was further tested for its in vitroCOX-1/COX-2 inhibitory activity. Compound 7cshowed similar inhibitory activities against COX-1 and COX-2 isoenzymes. The structural features that ensure the dual inhibition of COX-1 and COX-2 were elucidated using molecular docking studies. Overall, the ring closing of 2-pyridone pattern Itransformed this highly selective COX-2 inhibitor into a dual COX inhibitor (7c), which could serve as a model for determining selectivity for COX-2.

Selective prodrug activation at a tumor site is crucial to maximise the efficiency of chemotherapy approaches and minimise side effects due to off-site activation. In this paper, a new prodrug activation strategy is reported based on the bioorthogonal Staudinger reaction. The feasibility of this prodrug activation strategy was initially demonstrated using 9-azido sialic acid 4as a trigger and two novel triphenylphosphine-modified N-mustard-PRO 10and doxorubicin-PRO 12prodrugs in an HPLC-monitored release study. Then, the azide reporter group was introduced on cancer cells' surfaces through metabolic glycoengineering of sialic acid-rich surface glycans using azide-modified monosaccharides (9-azido sialic acid 4, tetra-O-acetylated-9-azido sialic acid 5and tetra-O-acetyl azidomannosamine). Next, the N-mustard-PRO 10and doxorubicin-PRO 12prodrugs were employed in vitrowith the bioengineered cells, and activation of the prodrugs, which allowed selective release of the cytotoxic moiety at the tumour cell, was assessed. Release of the parent drugs from the prodrugs was shown to be dependent on the level of metabolic labelling, where tetra-O-acetyl azidomannosamine allowed the highest level of azide reporter generation in tumor cells and led to full recovery of the parent cytotoxic drug's potency. The selectivity of azide expression on breast cancer MCF-7 cells versusnormal fibroblast L929 cells was also probed, with the 9-azido sialic acid and tetra-O-acetylated-9-azido sialic acid showing ∼17-fold higher azide expression on the former. Taken together, these data demonstrate the feasibility of the Staudinger reaction for selective activation of prodrugs targeted to the MCF-7 breast cancer cells.

Hederagenin is a pentacyclic triterpenoid isolated from plants and widely distributed in a variety of medicinal plants. By integrating and analyzing external related literature reports, the latest research progress on the pharmacological effects and structural modification of hederagenin was reviewed. Hederagenin has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antidepressant, anti-neurodegenerative, antihyperlipidemic, antidiabetic, anti-leishmaniasis, and antiviral activities. Among them, it shows high potential in the field of anti-tumor treatment. This paper also reviews the structural modifications of hederagenin, including carboxyl group modifications and two hydroxyl group modifications. Future research on hederagenin will focus on prolonging its half-life, improving its bioavailability and structural modification to enhance its pharmacological activity, accelerating the preclinical research stage of hederagenin for it to enter the clinical research stage as soon as possible.

Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the Ptpn11gene, which regulates cell growth, differentiation and apoptosis viamodulating various signaling pathways, such as the RAS/ERK signaling pathway, and participates in the PD-1/PD-L1 pathway governing immune surveillance. It has been recognized as a breakthrough antitumor therapeutic target. Besides, numerous studies have shown that SHP2 plays an important role in the regulation of inflammatory diseases. However, inhibitors targeting the active site of SHP2 lack drug-likeness due to their low selectivity and poor bioavailability, thus none has advanced to clinical development. Recently, allosteric inhibitors that stabilize the inactive conformation of SHP2 have achieved breakthrough progress, providing the clinical proof for the druggability of SHP2 as an antitumor drug target. This paper reviews the recently reported design and discovery of SHP2 small molecule inhibitors, focused on the structure–activity relationship (SAR) analysis of several representative SHP2 inhibitors, outlining the evolution and therapeutic potential of the small molecule inhibitors targeting SHP2.

Pyrazole is a five-membered heterocycle bearing two adjacent nitrogen atoms. Both pharmaceutical agents and natural products with pyrazole as a nucleus have exhibited a broad spectrum of biological activities. In the last few decades, more than 40 pyrazole-containing drugs have been approved by the FDA for the treatment of a broad range of clinical conditions including celecoxib (anti-inflammatory), CDPPB (antipsychotic), difenamizole (analgesic), etc.Owing to the unique physicochemical properties of the pyrazole core, pyrazole-containing drugs may exert better pharmacokinetics and pharmacological effects compared with drugs containing similar heterocyclic rings. The purpose of this paper is to provide an overview of all the existing drugs bearing a pyrazole nucleus that have been approved or in clinical trials, involving their pharmacological activities and SAR studies.

Mitogen-activated protein kinases (MAPKs) govern various cellular programs and crucial intermediate pathways in signaling. Microtubule affinity-regulating kinase 4 (MARK4) is a part of the kinase family recognized for actively phosphorylating neural microtubule-associated proteins (MAPs) like MAP2, MAP4 and most importantly, tau. The Ser/Thr kinase MARK4 overexpression is associated with various life-threatening conditions such as neurodegenerative disorders, diabetic neuropathy, and cancer. Functionally, MARK4 is correlated with many important signaling cascades and transcription factors contributing to neurodegeneration and cancer onset and progression. Serotonin is a key molecule associated with regulating mood, stress, and various behavioral aspects. Low serotonin levels promote the progression of neurological and psychotic disorders, which is also a consequence of tau accumulation. MARK4 being a major contributor to phosphorylating tau, leading to its accumulation, and contributing to tauopathy, is targeted for inhibition by serotonin. The study deals with the inhibition of MARK4 by serotonin using combined computational and experimental studies. The results presented in this paper provide strong evidence for the direct physical binding of serotonin to recombinant MARK4 and subsequent inhibition of its kinase activity. In addition, we have performed molecular docking, followed by 100 ns MD simulations of MARK4 in the presence of serotonin, to estimate the stability of the protein–ligand complex. Since MARK4 is a potential drug target and can be exploited for drug design and discovery for cancer and neurodegenerative disorders, the results presented here are of interest and may be further exploited for Alzheimer's disease (AD) and other neurodegenerative diseases.

Pirfenidone (PFD) was the first approved drug by FDA for the treatment of idiopathic pulmonary fibrosis (IPF). However, the rapid metabolism of 5-methyl of PFD increases the risk of side effects in clinics. Thus, in this paper, a common practice that a stable amide bond linking various groups used to replace 5-methyl of PFD in medicinal chemistry was applied, and total 18 PFD derivatives were synthesized. All compounds were investigated for their antiproliferation activities against NIH3T3 cells and the structure–activity relationships of the target compounds were also discussed. Among them, YZQ17possessed potent antiproliferation activity compared to PFD and better potency in inhibiting TGF-β-induced migration of NIH3T3 cells at a much lower concentration than that of PFD. In addition, YZQ17dramatically inhibited the expression levels of fibrotic markers α-SMA, collagen I, and fibronectin. Moreover, further mechanistic studies confirmed that YZQ17exhibited this considerable anti-fibrosis activity viathe TGF-β/Smad2/3 dependent pathway. Finally, the results of human and rat liver microsomes assay in vitroand pharmacokinetic assay in rats confirmed that YZQ17showed better pharmacokinetics than that of PFD. Collectively, the preliminary study of PFD derivatives modified by the amide group indicated that YZQ17could be regarded as a lead compound for further investigation and optimization.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a typical survival time between three to five years. Two drugs, pirfenidone and nintedanib have been approved for the treatment of IPF, but they have limited efficacy. Thus, the development of new drugs to treat IPF is an urgent medical need. In this paper we report the discovery of a series of orally active pyrimidin-4(3H)-one analogs which exhibit potent activity in in vitroassays. Among them, HEC-866 showed promising efficacy in rat IPF models. Since HEC-866 also had good oral bioavailability, a long half-life and favorable long-term safety profiles, it was selected for further clinical evaluation.

The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.

This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine. S-MGBs have been found to be active against many different organisms, however, selective antiparasitic activity is required. A panel of seven truncated S-MGBs was prepared and the activities examined against a number of clinically relevant organisms including several bacteria and parasites. The effect of the truncation strategy on S-MGB aggregation in aqueous environment was also investigated using 1H inspection and DOSY experiments. A lead compound, a truncated S-MGB, which possesses significant activity only against trypanosomes and Leishmaniahas been identified for further study and was also found to be less affected by aggregation compared to its full-length analogue.

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

One of the key motifs of type I kinase inhibitors is their interactions with the hinge region of ATP binding sites. These interactions contribute significantly to the potency of the inhibitors; however, only a tiny fraction of the available chemical space has been explored with kinase inhibitors reported in the last twenty years. This paper describes a workflow utilizing docking with rDock and dynamic undocking (DUck) for the virtual screening of fragment libraries in order to identify fragments that bind to the kinase hinge region. We have identified 8-amino-2H-isoquinolin-1-one (MR1), a novel and potent hinge binding fragment, which was experimentally tested on a diverse set of kinases, and is hereby suggested for future fragment growing or merging efforts against various kinases, particularly MELK. Direct binding of MR1to MELK was confirmed by STD-NMR, and its binding to the ATP-pocket was confirmed by a new competitive binding assay based on microscale thermophoresis.