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Abstract: Structure elucidation plays a critical role across the landscape of medicinal chemistry, including medicinal inorganic chemistry. Herein, we discuss the importance of structure elucidation in drug development and then provide three vignettes that capture key instances of its relevance in the development of biologically active inorganic compounds. In the first, we describe the exploration of the biological activity of the trinuclear Ru compound called ruthenium red and the realization that this activity derived from a dinuclear impurity. We next explore the development of Au‐based antitubercular and antiarthritic drugs, which features a key step whereby ligands were discovered to bind to Au through S atoms. The third exposition traces the development of As‐based antiparasitic drugs, a key step of which was the realization that the reaction of arsenic acid and aniline does not produce an anilide of arsenic acid, as originally thought, but rather an amino arsonic acid. These case studies provide the motivation for an outlook in which the development of Sb‐based antiparasitic drugs is described. Although antileishmanial pentavalent antimonial drugs remain in widespread use to this day, their chemical structures remain unknown.

Target-first drug discovery relies heavily on protein structure information, which severely limits its application. In recent years, fragment-based drug Design (FBDD) has been identified as an alternative solution, where screening of smaller molecules for lower affinity allowed the use of focused libraries with a higher hit rate. It is shown that coupling an sp2-rich heteroaromatic group with a monofunctional sp3-rich core gives fragments (186 examples) with advantageous physical-chemical properties, covering a chemical space often neglected in traditional libraries. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide and is considered a major public health problem. Despite the significant advances in cancer research, the conventional cancer treatment approaches often lead to serious side effects that affect the quality of life of cancer patients. Thus, searching for new alternatives for cancer treatment is crucial to minimize these problems. Chalcone‐sulfonamide hybrids display a range of biological activities and have been widely investigated for their anticancer potential, being considered promising molecules for cancer treatment. This systematic review aimed to summarize the information available in the literature about the anticancer potential of chalcones‐sulfonamides in vitro and in vivo and their mechanisms of action. Our analysis demonstrated that chalcones‐sulfonamides have relevant cytotoxic potential against different cancer cell lines in vitro, especially against the human colorectal carcinoma cell line HCT‐116. These molecules have also reduced tumor growth in vivo. Some chalcones‐sulfonamides had improved cytotoxicity after chemical modification and could become more selective or even more potent than reference chemotherapeutics. The mechanisms underlying these effects demonstrated that chalcones‐sulfonamides may lead to cell death by different pathways, predominantly via apoptosis or necroptosis. This review may encourage researchers to advance studies with chalcones‐sulfonamides, especially to elucidate their mechanisms of action, contributing to the development of new alternatives to cancer treatment. Summary: Several studies have demonstrated that chalcones‐sulfonamides have promising anticancer potential, with different suggestions of mechanisms of action. However, no study has combined and analyzed these results. This systematic review discussed the anticancer potential of chalcones‐sulfonamides and their main mechanisms of action based on the results of different scientific publications. Adding functional groups to the chemical structure of chalcones‐sulfonamides can improve their cytotoxicity and selectivity. These molecules can exert their anticancer effects through several mechanisms, especially through ROS generation, triggering cell death pathways like apoptosis or necroptosis. This review may encourage researchers to perform detailed investigations about the mechanisms of these molecules to finally understand their pathways and contribute to the development of new drugs for cancer therapy. [ABSTRACT FROM AUTHOR]

Since Strecker's discovery of multicomponent reactions (MCRs) in 1850, the strategy of applying an MCR approach has been in use for over a century. Due to their ability to quickly develop molecular diversity and structural complexity of interest, MCRs are considered an efficient approach in organic synthesis. Although MCRs such as the Ugi, Passerini, Biginelli, and Hantzsch reactions are widely studied, this review emphasizes the significance of selective MCRs to elegantly produce organic compounds of potential use in medicinal chemistry and industrial and material science applications, as well as the use of the MCR approach to sustainable methods. During synthesis, MCRs provide advantages such as atom economy, recyclable catalysts, moderate conditions, preventing waste, and avoiding solvent use. MCRs also reduce the number of sequential multiple reactions to one step. [ABSTRACT FROM AUTHOR]

The 2,2‐difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2‐difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2‐difluoro‐ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2‐difluoroethylation methods and allows access to a wide range of 2,2‐difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine. [ABSTRACT FROM AUTHOR]

Automated batch and flow setups are well‐established for high throughput experimentation in both thermal chemistry and photochemistry. However, the development of automated electrochemical platforms is hindered by cell miniaturization challenges in batch and difficulties in designing effective single‐pass flow systems. In order to address these issues, we have designed and implemented a new, slug‐based automated electrochemical flow platform. This platform was successfully demonstrated for electrochemical C−N cross‐couplings of E3 ligase binders with diverse amines (44 examples), which were subsequently transferred to a continuous‐flow mode for confirmation and isolation, showing its applicability for medicinal chemistry purposes. To further validate the versatility of the platform, Design of Experiments (DoE) optimization was performed for an unsuccessful library target. This optimization process, fully automated by the platform, resulted in a remarkable 6‐fold increase in reaction yield. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance (AMR) represents a pressing global health challenge with implications for developmental progress, as it increasingly manifests within pathogenic bacterial populations. This phenomenon leads to a substantial public health hazard, given its capacity to undermine the efficacy of medical interventions, thereby jeopardizing patient welfare. In recent years, an increasing number of machine learning methods have been employed to predict antimicrobial resistance. However, these methods still pose challenges in single-drug resistance prediction. This study proposed an effective model for predicting antimicrobial resistance to E. Coli by utilizing the eXtreme Gradient Boosting model (XGBoost), among ten other machine learning methods. The experimental results demonstrate that XGBoost outperforms other machine learning classification methods, particularly in terms of precision and hamming loss, with scores of 0.891 and 0.110, respectively. Our study explores the existing machine learning models for predicting antimicrobial resistance (AMR), thereby improving the diagnosis as well as treatment of infections in clinical settings. [ABSTRACT FROM AUTHOR]

Baclofen is an active pharmaceutical ingredient used for the treatment of muscle spasticity. We describe our efforts to develop a novel synthetic approach through C–C bond formation and a cost-effective route to baclofen. The synthesis involved a two-step approach through C–C bond formation using the extensively and commercially available starting material 4-chlorobenzyl cyanide with chloroacetic acid as a reagent in an aprotic solvent, followed by reduction of the nitrile functional group. The synthetic route to baclofen has been demonstrated to be commercially viable, cost-effective, and environmentally friendly. Execution of the developed process led to the isolation of (+)-baclofen in an overall yield of 60% at a multikilogram scale with >99.5% HPLC purity. This article also discusses the cost-effectiveness of the process, the impurity profiling, and the product quality. [ABSTRACT FROM AUTHOR]

A key goal of organic chemistry is to develop new principles for the control of reactions, which can be used to create promising materials demanded in all fields of scientific research and industry. This review is an overview of the scientific advances, which have been made by the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences in the past decade within the framework of current trends in organic chemistry. The review covers the results, which are significant for fundamental research and hold great promise for the application in different areas, from the production of materials, petrochemistry, and chemical ecology to medicine, agriculture, and food industry. [ABSTRACT FROM AUTHOR]

Isatin, a versatile heterocyclic compound, has emerged as a key player in synthetic and pharmaceutical chemistry due to its diverse pharmacological properties. Originally synthesized in 1841, isatin has been found in various natural sources and serves as a crucial pharmacophore for the development of synthetic compounds. This review provides a comprehensive overview of the anti-infective properties of isatin, covering its synthesis methods, structural characteristics, reactivity, and diverse biological activities. Synthesis methods such as the Sandmeyer, Stolle, Martinet, and Gassman approaches are discussed, highlighting their importance in accessing isatin derivatives. Structural characteristics, including tautomerization and spectral studies, are elucidated to provide insights into the compound's behavior. The reactivity of isatin at key sites influences its biological activity and synthetic versatility, underscoring its significance in medicinal chemistry research. Moreover, isatin exhibits promising antibacterial, antiviral, and antiparasitic activities, making it a potential candidate for the development of novel anti-infective agents. Through a thorough exploration of isatin's multifaceted properties, this review aims to contribute to the development of innovative strategies for infectious disease management. [ABSTRACT FROM AUTHOR]

Chemokine receptors are relevant targets for a multitude of immunological diseases, but drug attrition for these receptors is remarkably high. While many drug discovery programs have been pursued, most prospective drugs failed in the follow‐up studies due to clinical inefficacy, and hence there is a clear need for alternative approaches. Allosteric modulators of receptor function represent an excellent opportunity for novel drugs, as they modulate receptor activation in a controlled manner and display increased selectivity, and their pharmacological profile can be insurmountable. Here, we discuss allosteric ligands and their pharmacological characterization for modulation of chemokine receptors. Ligands are included if (1) they show clear signs of allosteric modulation in vitro and (2) display evidence of binding in a topologically distinct manner compared to endogenous chemokines. We discuss how allosteric ligands affect binding of orthosteric (endogenous) ligands in terms of affinity as well as binding kinetics in radioligand binding assays. Moreover, their effects on signaling events in functional assays and how their binding site can be elucidated are specified. We substantiate this with examples of published allosteric ligands targeting chemokine receptors and hypothetical graphs of pharmacological behavior. This review should serve as an effective starting point for setting up assays for characterizing allosteric ligands to develop safer and more efficacious drugs for chemokine receptors and, ultimately, other G protein‐coupled receptors. [ABSTRACT FROM AUTHOR]

In order to detemine the anti-diabetic effect and potential mechanism of a novel soluble epoxide hydrolas inhibitor (A34) on diabetic mice. Type 1 diabetes mellitus (T1DM) mice were induced by streptozotocin (50 mg/(kg·d) for 5 days, ip.)and the hypoglycemic effect of A34 were evaluated by water and food intake, non-fasting and fasting blood glucose, glucose tolerance and plasma insulin level in diabetic mice after water administration.The underlying mechanism was explored via measuring the expression level of sEH in islets, the morphological change of islets and the concerntration of cytokines INF-γ and IL-4 in plasma. Compared with diabetic model group, the water and food intake(p＜0.01, p＜0.05), blood glucose (p＜0.01), glucose tolerance (p＜0.01) and plasma insulin level (p＜0.05 ) were improved in A34 group. Additionally, A34 could protect pancreatic islet morphology, suppress sEH expression in islet (p＜0.01), reduce the ratio of INF-γ to IL-4 in plasma(p＜0.05 ). These results showed that A34 prevents hyperglycemia and β-cell dysfunction through regulating the dynamic balance of pro-inflammatory and anti-inflammatory cytokines in diabetic mice.

Context Epigallocatechin-3-gallate (EGCG), the predominant catechin in green tea, has shown the potential to combat various types of cancer cells through its ability to modulate multiple signaling pathways. However, its low bioavailability and rapid degradation hinder its clinical application.Objective This review explores the potential of nanoencapsulation to enhance the stability, bioavailability, and therapeutic efficacy of EGCG in cancer treatment.Methods We searched the PubMed database from 2019 to the present, using ‘epigallocatechin gallate’, ‘EGCG’, and ‘nanoparticles’ as search terms to identify pertinent literature. This review examines recent nano-engineering technology advancements that encapsulate EGCG within various nanocarriers. The focus was on evaluating the types of nanoparticles used, their synthesis methods, and the technologies applied to optimize drug delivery, diagnostic capabilities, and therapeutic outcomes.Results Nanoparticles improve the physicochemical stability and pharmacokinetics of EGCG, leading to enhanced therapeutic outcomes in cancer treatment. Nanoencapsulation allows for targeted drug delivery, controlled release, enhanced cellular uptake, and reduced premature degradation of EGCG. The studies highlighted include those where EGCG-loaded nanoparticles significantly inhibited tumor growth in various models, demonstrating enhanced penetration and efficacy through active targeting mechanisms.Conclusions Nanoencapsulation of EGCG represents a promising approach in oncology, offering multiple therapeutic benefits over its unencapsulated form. Although the results so far are promising, further research is necessary to fully optimize the design of these nanosystems to ensure their safety, efficacy, and clinical viability.

Targeted protein degradation (TPD) has emerged as an important strategy to target disease-relevant proteins that were previously considered difficult to drug or even undruggable. Cereblon (CRBN) plays an outsized role in TPD as a preferred degradation-inducing effector protein for several reasons, including its anticipated broad protein substrate scope and its ligandability with drug-like small molecules. Notably, CRBN-based molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs) have shown success in clinical trials and, in some cases, as approved drugs. Thus, the interest in CRBN ligands within the pharmaceutical industry and academia has increased dramatically in recent years, highlighting the need for robust synthetic approaches towards them. This short review summarizes tactics and strategies to synthesize CRBN ligands, including the most recent developments in the field. Particular emphasis is put on the construction and direct functionalization of key CRBN binding motifs such as glutarimides and dihydrouracils. 1 Introduction 2 Cereblon Ligands with Glutarimide Binding Motif 3 Cereblon Ligands with Dihydrouracil Binding Motif 4 Cereblon Ligands with Other Binding Motifs 5 Conclusions and Outlook [ABSTRACT FROM AUTHOR]

The concept of bioisostere replacement is of paramount importance in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast area of chemical space of biological importance) in medicinal chemistry is the 2-phenethyl moiety, a key component of diverse drug-like entities. Although the core 2-phenethylamine structure has been recognized by the drug discovery community, little attention has been given to the various ring-based rescaffolding procedures that can be conducted with this unit. In this regard, a review on the use of 2-heteroarylethylamines displaying pharmacological activity is reported. A detailed description of flexible, amine-opened motifs is provided, that describes therapeutic targets and other potent bioactive examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community.

Abstract Background The purpose of this study was to evaluate the effectiveness and efficiency of implementing a data-driven blended online-offline (DDBOO) teaching approach in the medicinal chemistry course. Methods A total of 118 third-year students majoring in pharmacy were enrolled from September 2021 to January 2022. The participants were randomly assigned to either the DDBOO teaching group or the traditional lecture-based learning (LBL) group for medicinal chemistry. Pre- and post-class quizzes were administered, along with an anonymous questionnaire distributed to both groups to assess students’ perceptions and experiences. Results There was no significant difference in the pre-class quiz scores between the DDBOO and LBL groups (T=-0.637, P = 0.822). However, after class, the mean quiz score of the DDBOO group was significantly higher than that of the LBL group (T = 3.742, P

A base-induced synthesis of 2-(4-(2-(phenylthio)ethyl)piperazinyl) acetonitriles by reaction of disulfides, 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride and trimethylsilyl cyanide is reported. The scope of the method is demonstrated with 30 examples. The reaction mechanism research indicates that the three-component reaction would be a SN2 reaction. The products exhibit good activities towards advanced synthesis of aqueous soluble acyl-CoA: cholesterol O-acyltransferase-1 (ACAT-1) inhibitors. Our work is superior as it uses less-odor disulfides as carbon sources and EtOH as solvent in a water and dioxygen insensitive reaction system, followed by a simple purification process. [ABSTRACT FROM AUTHOR]

Sickle Cell Anemia (SCA), is an inherited hemoglobinopathy characterized by the presence of an abnormal hemoglobin (HbS), being the most prevalent sickle cell disease (SCD). SCA is characterized by vascular endothelial dysfunction, which contributes significantly to various clinical conditions, including but not limited to pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke. The pathophysiology of endothelial dysfunction (ED) in SCA is a multifaceted process involving a chronic inflammatory and hypercoagulable state. Key factors include hemolysis-associated elements like reduced arginine and nitric oxide (NO) availability, elevated levels of vascular adhesion molecules, the uncoupling effect of NO synthase, heightened arginase activity, an environment characterized by oxidative stress with the production of reactive oxygen and nitrogen species, and occurrences of ischemia-reperfusion injury, along with apolipoprotein A-1 depletion. The urgency for novel interventions addressing ED is evident. Presently, there is a focus on investigating small molecules that disrupt the arginine-nitric oxide pathway, exhibiting anti-inflammatory and antioxidant properties while diminishing levels of cellular and vascular adhesion molecules. In this mini-review article, we delve into the progress made in strategies for treating ED in SCD with the aim of cultivating insights for drug design. [Display omitted] • ED is a vasculopathy found in SCD patients responsible for pulmonary arterial hypertension, priapism, and leg ulcers. • Low NO bioavailability, activated endothelial cells, and high levels of ROS are the main characteristics in ED. • NO-donors, sGC stimulators and activators, antioxidants, supplementation of vitamins and arginine are the focus of this review. • FDA approved drugs such as HU and l-glutamine also play an important role in ED, ameliorating the oxidant profile. [ABSTRACT FROM AUTHOR]

Porphyrin atropisomerism, which arises from restricted σ‐bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20‐tetrakis(o‐hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry. [ABSTRACT FROM AUTHOR]

The terpolymers of N-vinylpyrrolidone (VP) with acrylic acid and triethylene glycol methacrylate were synthesized with more than 90% yield by radical copolymerization in ethanol from monomeric mixtures of different molar composition (98:2:2, 95:5: 2 and 98:2:5) and their monomer composition, absolute molecular masses and hydrodynamic radii in aqueous media were determined. Using the MTT test, these terpolymers were established to be low toxic for non-tumor Vero cells and HeLa tumor cells. Polymer compositions of hydrophobic dye methyl pheophorbide a (MPP) based on studied terpolymers and linear polyvinylpyrrolidone (PVP) were obtained and characterized in water solution. Quantum-chemical modeling of the MPP-copolymer structures was conducted, and the possibility of hydrogen bond formation between terpolymer units and the MPP molecule was shown. Using fluorescence microscopy, the accumulation and distribution of polymer particles in non-tumor (FetMSC) and tumor (HeLa) cells was studied, and an increase in the accumulation of MPP with both types of particles was found. [ABSTRACT FROM AUTHOR]

The unique structural and physicochemical properties of adamantane and its derivatives have attracted considerable attention in the field of medicinal chemistry. Substituting phenyl rings for adamantane or its derivatives has provided a promising strategy to introduce lipophilicity and escape the 'flat land' of modern drug discovery. Additionally, the unique three-dimensional structure of adamantane facilitates the precise positioning of substituents allowing for a more effective exploration of drug targets. Evidently, we have seen an increased use of adamantane in pharmaceutically relevant molecules. The following Account highlights our group's research in five drug discovery programs over the past 15 years showcasing the use of adamantane and its analogues in these studies. Adamantyl-containing compounds have proven to be effective ligands at a range of therapeutic targets. Its unique structural and physicochemical properties provide a promising strategy to increase lipophilicity and introduce three-dimensionality to a structure. The following Account highlights our group's research in five drug discovery programs showcasing the use of adamantane. (Image credit: Chianna Dane.) This article belongs to the 10th Anniversary Collection of RACI and AAS Award papers. [ABSTRACT FROM AUTHOR]

To increase the success rate of drug discovery, one practical strategy is to begin molecular hybridisation. The presence of two or more pharmacophores in a single unit leads to a pharmacological potency greater than the sum of each individual moiety's potency. Heterocyclic compounds are very widely distributed in nature and are essential for life activities. Benzimidazole and oxadiazole are privileged structures in medicinal chemistry and are widely used in drug discovery and development due to their vast biological properties. The drug‐like properties (like pharmacokinetics and pharmacodynamics) of the individual scaffolds can be improved by benzimidazole–oxadiazole chimeric molecules via a molecular hybridisation approach. Benzimidazole and oxadiazole cores can either be fused or incorporated using either functional groups/bonds. Over the last few decades, drug discovery scientists have predicted that these moieties could be interconnected to yield a novel or modified hybrid compound. Benzimidazole and oxadiazole hybrids were identified as the most potent anticancer, antimicrobial, anti‐inflammatory, antioxidant, anticonvulsant, antidepressant, antihypertensive and antitubercular agents. In this context, the present review describes the biological properties of benzimidazole–oxadiazole (1,3,4 and 1,2,4) hybrids, their possible structure–activity relationship and the mechanism of action studies presented. This review article is intended to stimulate fresh ideas in the search for rational designs of more active and less toxic benzimidazole–oxadiazole hybrid prospective therapeutic candidates, as well as more effective diagnostic agents and pathologic probes. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the effectiveness and efficiency of implementing a data-driven blended online-offline (DDBOO) teaching approach in the medicinal chemistry course. Methods: A total of 118 third-year students majoring in pharmacy were enrolled from September 2021 to January 2022. The participants were randomly assigned to either the DDBOO teaching group or the traditional lecture-based learning (LBL) group for medicinal chemistry. Pre- and post-class quizzes were administered, along with an anonymous questionnaire distributed to both groups to assess students' perceptions and experiences. Results: There was no significant difference in the pre-class quiz scores between the DDBOO and LBL groups (T=-0.637, P = 0.822). However, after class, the mean quiz score of the DDBOO group was significantly higher than that of the LBL group (T = 3.742, P < 0.001). Furthermore, the scores for learning interest, learning motivation, self-learning skill, mastery of basic knowledge, teamwork skills, problem-solving ability, innovation ability, and satisfaction, as measured by the questionnaire, were significantly higher in the DDBOO group than in the traditional group (all P < 0.05). Conclusion: The DDBOO teaching method effectively enhances students' academic performance and satisfaction. Further research and promotion of this approach are warranted. [ABSTRACT FROM AUTHOR]

Oleanolic acid (OA) is a vegetable chemical that is present naturally in a number of edible and medicinal botanicals. It has been extensively studied by medicinal chemists and scientific researchers due to its biological activity against a wide range of diseases. A significant number of researchers have synthesized a variety of analogues of OA by modifying its structure with the intention of creating more potent biological agents and improving its pharmaceutical properties. In recent years, chemical and enzymatic techniques have been employed extensively to investigate and modify the chemical structure of OA. This review presents recent advancements in medical chemistry for the structural modification of OA, with a special focus on the biotransformation, semi-synthesis and relationship between the modified structures and their biopharmaceutical properties. [ABSTRACT FROM AUTHOR]

In this study, synthesis, characterization, optical, and in silico medicinal properties of a Schiff base compound, 4-((4,5-difluoro-2-hydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-2,3-dihydro-1H-pyrazol-3-ol, were reported. X-ray, FTIR, and UV-vis spectra, including computational and experimental data, were used to characterize the Schiff base molecule. Pharmacophore analysis of the molecular structure was performed to investigate the active interaction centers that can interact with macromolecular biological targets. Since the synthesized Schiff base is not centrosymmetric, the NLO material potential was evaluated using the DFT approach, and it showed higher NLO efficacy compared to the reference molecule urea. Potential biological targets of the title compound were investigated using a web server (LigTMap). Top twelve candidate targets, including transferase, hydrolase, and kinase targets, were identified. According to the docking scores, the most potent target of the title compound was determined as vascular endothelial growth factor receptor 2 (PDB: 3VO3). [ABSTRACT FROM AUTHOR]

A series of 5-Aryl-1,2,4-triazole derivatives linked by Quinazolin-4-one thioether were designed and synthesized through condensation reactions. The structure of the synthesized compounds was characterized using IR, NMR, and mass spectroscopy. The synthesized triazoles, coded as NSS-T, were evaluated for their in silico biological profile through molecular docking and for their in vitro anticancer and antimicrobial activity. In silico molecular modeling studies for the synthesized hybrids have shown good molecular interactions with EGFR and HDAC6 cancer targets and Sterol 14-α demethylase fungal target. From in vitro studies, all compounds were found to be active against MCF-7 (breast), A549 (lung), SiHa (cervix), and Colo 205 (colon) besides inhibitory active against Gram-negative, Gram-positive bacterial strains as well as selected fungal strains (C. albicans). [ABSTRACT FROM AUTHOR]

Drawing from the author’s years of scientific research and graduate mentorship, this paper examines the challenges encountered in the training of medicinal chemistry graduate students. It also outlines effective strategies of cultivating expertise in this field. [ABSTRACT FROM AUTHOR]

ABSTRACT Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in de novo guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether in vivo inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy in vivo against Acinetobacter baumannii mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of A. baumannii, Staphylococcus aureus, and Escherichia coli GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear in vivo efficacy of these small molecule GuaB inhibitors in a model of A. baumannii infection validates GuaB as an essential antibiotic target.IMPORTANCEThe emergence of multidrug-resistant bacteria worldwide has renewed interest in discovering antibiotics with novel mechanism of action. For the first time ever, we demonstrate that pharmacological inhibition of de novo guanine biosynthesis is bactericidal in a mouse model of Acinetobacter baumannii infection. Structural analyses of novel inhibitors explain differences in biochemical and whole-cell activity across bacterial clades and underscore why this discovery may have broad translational impact on treatment of the most recalcitrant bacterial infections.

Since Strecker’s discovery of multicomponent reactions (MCRs) in 1850, the strategy of applying an MCR approach has been in use for over a century. Due to their ability to quickly develop molecular diversity and structural complexity of interest, MCRs are considered an efficient approach in organic synthesis. Although MCRs such as the Ugi, Passerini, Biginelli, and Hantzsch reactions are widely studied, this review emphasizes the significance of selective MCRs to elegantly produce organic compounds of potential use in medicinal chemistry and industrial and material science applications, as well as the use of the MCR approach to sustainable methods. During synthesis, MCRs provide advantages such as atom economy, recyclable catalysts, moderate conditions, preventing waste, and avoiding solvent use. MCRs also reduce the number of sequential multiple reactions to one step.

Pyrrolo[2,3-c]pyridines (6-azaindoles) are the most promising nitrogen-containing heterocyclic compounds in the field of drug development. Exhibiting extraordinary versatility as pharmacophores, they are widely used in the development of kinase inhibitors, antiproliferative agents, and as potential therapeutic agents for the treatment of various diseases, including cancer and Alzheimer’s disease. A large number of works focusing on new methods and approaches in the synthesis of 6-azaindoes, as well as on the study of their biological activity, have been published worldwide. In our review, we tried to classify all currently known strategies for the construction of the 6-azaindole core, which were published within the last 15 years, the chemical diversity of the derivatives obtained, and their therapeutic potential in the context of medicinal chemistry. We hope that this work will generalize and facilitate the understanding of the strategy for the synthesis of pyrrolo[2,3-c]pyridines, as well as help scientists in their further research in the direction of 6-azaindoles.

Carboxyhydrazides are widely used in medicinal chemistry because of their medicinal properties and many drugs have been developed containing this functional group. A suitable intermediate to obtain potential hydrazide drug candidates is the title compound 5-hydroxypentanehydrazide, C5H12N2O2 (1). The aliphatic compound can react both via the hydroxyl and hydrazide moieties forming derivatives, which can inhibit Mycobacterium tuberculosis catalase-peroxidase (KatG) and consequently causes death of the pathogen. In this work, the hydrazide was obtained via a reaction of a lactone with hydrazine hydrate. The colourless prismatic single crystals belong to the orthorhombic space group Pca21. Regarding supramolecular interactions, the compound shows classic medium to strong intermolecular hydrogen bonds involving the hydroxyl and hydrazide groups. Besides, the three-dimensional packing also shows weak H...H and C...H contacts, as investigated by Hirshfeld surface analysis (HS) and fingerprint plots (FP).

Pyridine derivatives have emerged as promising candidates in the field of biomedical research, showcasing a wide array of applications in drug development and therapeutic interventions. The recent advances in the design and utilization of pyridine derivatives, focusing on their diverse roles in biomedical applications is the key understanding in this study. The versatility of pyridine-based compounds has been leveraged to address various challenges in the realms of pharmaceuticals and medicinal chemistry, offering innovative solutions for improved healthcare outcomes. This review encompasses the synthesis methodologies of pyridine derivatives, elucidating key synthetic strategies that enable the tailoring of these compounds for specific biomedical purposes and medicinal properties. This underscores the recent advancements in understanding the pharmacokinetics and pharmacodynamics of pyridine derivatives, emphasizing their potential impact on the future landscape of biomedical research. The synthesis and application of these compounds represent a dynamic frontier in drug development, offering innovative solutions to address unmet medical needs and propel the field toward more effective and personalized therapies. Pyridine derivatives play an important role in bio-imaging applications for the diagnosis of various diseases. Pyridine-based macromolecules have great potential for the efficient and specific delivery of drugs.

Artificial intelligence has brought crucial changes to the whole field of natural sciences. Myriads of machine learning algorithms have been developed to facilitate the work of experimental scientists. Molecular property prediction and drug synthesis planning become routine tasks. Moreover, inverse design of compounds with tunable properties as well as on-the-fly autonomous process optimization and chemical space exploration became possible in silico. Affordable robotic platforms exist able to perform thousands of experiments every day, analyzing the results and tuning the protocols. Despite this, most of these developments get trapped at the stage of code or overlooked, limiting their use by experimental scientists. Meanwhile, visibility and the number of user-friendly tools and technologies available to date is too low to compensate for this fact, rendering the development of novel therapeutic compounds inefficient. In this Review, we set the goal to bridge the gap between modern technologies and experimental scientists to improve drug development efficacy. Here we survey advanced and easy-to-use technologies able to help medical chemists at every stage of their research, including those integrated in technological processes during COVID-19 pandemic motivated by the need for fast yet precise solutions. Moreover, we review how these technologies are integrated by industry and clinics to streamline drug development and production. These technologies already transform the current paradigm of scientific thinking and revolutionize not only medicinal chemistry, but the whole field of natural sciences.

Targeted protein degradation has recently gained widespread interest as both a novel therapeutic strategy and a useful tool in biomedical research. Targeted protein degraders are often sub-stoichiometric and do not require strong binding affinity for their targets, enabling access to previously inaccessible targets. Proteolysis-targeting chimeras (PROTACs) are one class of targeted protein degraders that promote degradation by recruiting a target protein to an E3-ligase complex via a heterobifunctional molecule. The modular nature of PROTACs allows for their rational design and systematic optimization. Here we suggest resources and methodologies for developing PROTAC degraders for researchers that may be new to the field. © 2022 Wiley Periodicals LLC.

Azetidines are valuable nitrogenous heterocycles. Herein, we disclose a strategy for the modular assembly of 3‐azetidines and related spirocyclic congeners featuring all‐carbon quaternary centers. This approach leverages titanacyclobutanes generated from ketones or alkenes. Halogenation of these organotitanium species gives rise to functionalized alkyl dihalides that can be subsequently captured by amines to afford azetidine building blocks. This strategy facilitated the synthesis of a small molecule anti‐tuberculosis drug. It also enabled access to carbon‐13 isotopologs of diazaspiro[3.3]heptane fragments that are challenging to prepare by any other means. [ABSTRACT FROM AUTHOR]

This document explores the use of late-stage functionalization (LSF) in medicinal chemistry, specifically focusing on the modification of drug molecules towards the end of synthesis. LSF allows for the rapid generation of diverse analogues and the exploration of structure-activity relationships (SAR). The document provides case studies of LSF applications, including the modification of compounds targeting the BTK enzyme and the GPR40 receptor. The authors emphasize the potential of LSF in expanding the chemical space around lead molecules and improving pharmacokinetic properties. They also discuss future opportunities for LSF in more complex synthetic contexts and the modification of other modalities such as peptides and oligonucleotides. [Extracted from the article]

Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ—metronidazole; MCZ—miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L. [ABSTRACT FROM AUTHOR]

We have developed a general and practical approach towards 2‐oxabicyclo[2.1.1]hexanes with two and three exit vectors via an iodocyclization reaction. The obtained compounds have been easily converted into the corresponding building blocks for use in medicinal chemistry. 2‐Oxabicyclo[2.1.1]hexanes have been incorporated into the structure of five drugs and three agrochemicals, and validated biologically as bioisosteres of ortho‐ and meta‐benzenes. [ABSTRACT FROM AUTHOR]

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion. [ABSTRACT FROM AUTHOR]

Among a large number of nitrogen-containing heterocyclic compounds, pyrazole is a privileged scaffold with the molecular formula C3H3N2H. It consists of a five-membered ring with 3-carbon atoms and 2-nitrogen atoms which are present in adjacent positions. The nucleus has attracted synthetic interest due to numerous pharmacological activities. This molecule is used as one of the basic moieties for leads in the area of drug discovery and development and thereby plays a vital role in the field of medicinal chemistry. The present review article highlights the SAR studies of potent compounds of pyrazole and its derivatives (2015–2022) reported as anti-inflammatory, anticancer, antidiabetic, anticonvulsant, antimicrobial, antimycobacterial, antineurodegenerative and antioxidant. Furthermore, a patent application published in this period is also discussed. Google, PubMed, Cochrane, Scopus, ResearchGate, Google Scholar, and Science Direct were primarily used for article search, whereas the databases used for the pyrazole patent were Espacenet, Google Patent, and SciFinder. More than one hundred thirty papers were screened after which inclusion and exclusion criteria were applied to make this review article. We hope the current review article can pave the way for the future drug design and development of pyrazole derivatives as a potential drug candidate. [ABSTRACT FROM AUTHOR]

Imidazoles are one of the keys of N‐heterocycle molecules that exist in the structure of many biomolecules. In this research project, we reported that Fe3O4@BisImid−CuBr nanocomposite is an attractive and efficient nanomagnetic catalyst to afford 2,4,5–triaryl imidazoles through reactions of 1,2–diketones and aldehydes in the presence of NH4OAc under ecofriendly conditions. The Fe3O4@BisImid−CuBr nanocomposite was readily fabricated by a simple method from available reagents and its structure was analyzed by spectroscopic techniques. SEM and TEM images affirmed the formation of particles in spherical shape and nanometer–size. Under this methodology, a diverse library of triaryl imidazoles were afforded with high yields in water. This synthetic methodology has significant features such as (a) high yields and high purity of the products (b) suitable reaction time (c) use of magnetic reusable nanocatalyst (d) high reusability of Fe3O4@BisImid−CuBr nanocatalyst and the performance of reactions in aqueous medium. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI) has emerged as a transformative tool in various fields, including medicinal chemistry and drug discovery. The integration of artificial intelligence (AI) and machine learning (ML) technologies in medicinal chemistry has revolutionized drug discovery processes. Among AI models, ChatGPT (Generative Pre‐trained Transformer) has shown remarkable capabilities in natural language understanding and generation. This review article delves into the potential applications and prospects of ChatGPT in the domain of medicinal chemistry, focusing on its contributions to drug discovery, compound design, virtual screening, target identification, and optimization of pharmacokinetic properties. ChatGPT′s ability to generate contextually relevant text makes it a valuable tool for data mining and analysis of vast chemical and biological information repositories. In this review article, the authors have discussed the challenges and ethical considerations associated with the implementation of ChatGPT 3.5 in medicinal chemistry research. Authors also extend their acknowledgment to ChatGPT (version 3.5) for its contribution in furnishing responses to the prompt, thereby shedding light on the applications of ChatGPT in the field of medicinal chemistry. The authors have analyzed the responses of ChatGPT. [ABSTRACT FROM AUTHOR]

Oxazoles are an important class of biologically active compounds in the pharmaceutical chemistry and are considered as the main structure of many biologically active compounds. Therefore, the development of efficient and ecofriendly catalytic systems for the preparation of thiazole derivatives is a key research topic in organic synthesis. During the last decade, chemistry science especially organic synthesis witnessed a huge revolution in the field of using magnetic nanocomposites as the catalyst. Magnetic nanoparticles not only have high stability, but also their surface can be easily modified and an efficient catalyst can be prepared from this method. In addition, the most important feature of magnetic nanocatalysts is their simple separation from the reaction mixture using only an external magnet. In these years, a series of magnetic nanocatalysts were reported for the synthesis of various derivatives of oxazoles, and in this article, we are going to review these methods and mention the characteristics of these catalytic systems. Based on our complete search in the literature, this is the first review-article on the application of magnetic nanocatalysts in the synthesis of oxazole derivatives. In our opinion, this review is a good source for synthetic chemists who work in the field of synthesis of oxazole derivatives and whose research is focused on magnetic nanocatalysts. [ABSTRACT FROM AUTHOR]

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA‐sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast‐deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic "hot spots". Furthermore, we report the discovery of the first‐in‐class inhibitor leads for hypoxia up‐regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of α-l-threofuranosyl guanosine 3'-triphosphate (tGTP), which is an important building block for the construction of artificial genetic polymers. The traditional method for synthesizing tGTP involves a laborious and time-consuming process. However, the authors propose an alternative synthetic route using commercially available 6-chloropurine-2-amine, which simplifies the synthesis and reduces the use of hazardous solvents. The authors also compare two different methods for preparing tGTP nucleotides and conclude that the pyrene pyrophosphate approach is preferred due to its fewer synthetic steps. This improved approach could be advantageous for the large-scale synthesis of guanosine nucleosides. [Extracted from the article]

This article discusses the synthesis and evaluation of the anti-hepatitis B virus (HBV) activity of novel nucleoside derivatives. Hepatitis B is a prevalent viral disease that affects millions of people worldwide and can lead to chronic disease and liver cancer. The article describes the synthesis of a 2'-deoxy-4'-thioguanosine derivative with a cyano group at the 4'-position, which exhibited significantly more potent anti-HBV activity than the parent nucleoside. This finding could guide the development of new anti-HBV agents. [Extracted from the article]

This article discusses recent advances in the synthesis of 5-(hetero)aryl uracil derivatives, which are important compounds in the field of life sciences. The article focuses on various synthesis strategies for these derivatives, including selective coupling of pre-functionalized uracils, transition-metal-catalyzed or photo-prompted modification of uracil moieties, substitution of unactivated uracils with (hetero)aromatic components, and oxidative coupling of un-functionalized uracils. The article also discusses specific coupling reactions, such as Negishi coupling and Suzuki-Miyaura coupling, that have been used to synthesize these compounds. The development of new derivatives and synthesis strategies for these compounds is of great interest due to their wide-ranging biological potential. [Extracted from the article]