Field Of Medicinal Chemistry Research Articles

Transition-Metal-Catalyzed Denitrogenative Annulation to Access High-Valued N-Heterocycles.

Over the past few years, the development of efficient methods to construct high-valued N-heterocyclic molecules have received massive attention owing to their extensive application in the areas of medicinal chemistry, drug discovery, natural product synthesis and so on. To access those high-valued N-heterocycles, many methods have been developed. In this context, transition-metal-catalyzed denitrogenative annulation of 1,2,3-triazoles and 1,2,3,4-tetrazoles has appeared as a powerful synthetic tool because it offers a step- and atom-economical route for the preparation of the nitrogen-rich molecules. Compared with the denitrogenative annulation of various 1,2,3-triazole frameworks, annulation of 1,2,3,4-tetrazole remains more challenging due to the inertness of the tetrazole moiety. This Review summarizes the significant achievements made in the field of denitrogenative annulation of various 1,2,3-triazoles and 1,2,3,4-tetrazoles including some pioneering examples in this area of research. We anticipate that this denitrogenative annulation reaction will find broad applications in the pharmaceutical industry, drug discovery and other fields of medicinal chemistry.

Synthesis, molecular docking and anticancer potential of azolium based salts and their silver complexes: DNA/BSA interaction studies and cell cycle analysis

Azolium based molten salts have widely been investigated for biological potentials and interestingly, their metal complexes are getting attention in the field of medicinal inorganic chemistry. Here, we report three binuclear molten salts (L1-L3) and their silver complexes (C1-C3), assured through spectroscopic and mass spectrometric approaches. Solvent dependent catecholase activity was studied in three different solvents which suggests that nature of solvent has potential impact on chemical reactivity of test compounds. Anticancer activity was investigated through MTT assay, fluorescence microscopic analysis, ROS generation, and cell cycle arrest assay against HeLa, MCF-7, HCT-116 and A549 cancer cell lines and results confirmed the superior anticancer potential of silver complexes from their precursor salts. The cytotoxicity was cell selective and dose-dependant against MCF-7 with IC50 of C1 6.28 ± 0.82 µM which outshone even from positive control 5-FU (12.87 ± 1.0 µM) and cisplatin (8.74 ± 0.52 µM). Biological behavior of C1 & C2 was predicted through molecular docking studies and it speculated lower binding energies of C1 i.e. −10.05 kcal/mol and −7.51 kcal/mol for DNA and BSA, respectively. The experimental study of drug-DNA and drug-BSA interaction confirmed the prediction of simulation results. In addition, the role of hydrophobicity of compounds in the cytotoxicity was established viz., how the lipophilic value affects the anticancer activity of complexes.

Synthetic Imidazopyridine-Based Derivatives as Potential Inhibitors against Multi-Drug Resistant Bacterial Infections: A Review.

Fused pyridines are reported to display various pharmacological activities, such as antipyretic, analgesic, antiprotozoal, antibacterial, antitumor, antifungal, anti-inflammatory, and antiapoptotic. They are widely used in the field of medicinal chemistry. Imidazopyridines (IZPs) are crucial classes of fused heterocycles that are expansively reported on in the literature. Evidence suggests that IZPs, as fused scaffolds, possess more diverse profiles than individual imidazole and pyridine moieties. Bacterial infections and antibacterial resistance are ever-growing risks in the 21st century. Only one IZP, i.e., rifaximin, is available on the market as an antibiotic. In this review, the authors highlight strategies for preparing other IZPs. A particular focus is on the antibacterial profile and structure-activity relationship (SAR) of various synthesized IZP derivatives. This research provides a foundation for the tuning of available compounds to create novel, potent antibacterial agents with fewer side effects.

Antiproliferative Activity Predictor: A New Reliable In Silico Tool for Drug Response Prediction against NCI60 Panel.

In vitro antiproliferative assays still represent one of the most important tools in the anticancer drug discovery field, especially to gain insights into the mechanisms of action of anticancer small molecules. The NCI-DTP (National Cancer Institute Developmental Therapeutics Program) undoubtedly represents the most famous project aimed at rapidly testing thousands of compounds against multiple tumor cell lines (NCI60). The large amount of biological data stored in the National Cancer Institute (NCI) database and many other databases has led researchers in the fields of computational biology and medicinal chemistry to develop tools to predict the anticancer properties of new agents in advance. In this work, based on the available antiproliferative data collected by the NCI and the manipulation of molecular descriptors, we propose the new in silico Antiproliferative Activity Predictor (AAP) tool to calculate the GI50 values of input structures against the NCI60 panel. This ligand-based protocol, validated by both internal and external sets of structures, has proven to be highly reliable and robust. The obtained GI50 values of a test set of 99 structures present an error of less than ±1 unit. The AAP is more powerful for GI50 calculation in the range of 4-6, showing that the results strictly correlate with the experimental data. The encouraging results were further supported by the examination of an in-house database of curcumin analogues that have already been studied as antiproliferative agents. The AAP tool identified several potentially active compounds, and a subsequent evaluation of a set of molecules selected by the NCI for the one-dose/five-dose antiproliferative assays confirmed the great potential of our protocol for the development of new anticancer small molecules. The integration of the AAP tool in the free web service DRUDIT provides an interesting device for the discovery and/or optimization of anticancer drugs to the medicinal chemistry community. The training set will be updated with new NCI-tested compounds to cover more chemical spaces, activities, and cell lines. Currently, the same protocol is being developed for predicting the TGI (total growth inhibition) and LC50 (median lethal concentration) parameters to estimate toxicity profiles of small molecules.

Enantioselective synthesis of N-alkylindoles enabled by nickel-catalyzed C-C coupling

Enantioenriched N-alkylindole compounds, in which nitrogen is bound to a stereogenic sp3 carbon, are an important entity of target molecules in the fields of biological, medicinal, and organic chemistry. Despite considerable efforts aimed at inventing methods for stereoselective indole functionalization, straightforward access to a diverse range of chiral N-alkylindoles in an intermolecular catalytic fashion from readily available indole substrates remains an ongoing challenge. In sharp contrast to existing C–N bond-forming strategies, here, we describe a modular nickel-catalyzed C–C coupling protocol that couples a broad array of N-indolyl-substituted alkenes with aryl/alkenyl/alkynyl bromides to produce chiral N-alkylindole adducts in single regioisomeric form, in up to 91% yield and 97% ee. The process is amenable to proceed under mild conditions and exhibit broad scope and high functional group compatibility. Utility is highlighted through late-stage functionalization of natural products and drug molecules, preparation of chiral building blocks.

New Methods for the Synthesis of 3-Aroylimidazo[1,2-a]Pyridines: A Review

Due to the high level of biological activity and other different interesting applications, 3-aroylimidazo[1,2-a]pyridines have received considerable attention in modern synthetic organic chemistry. This review is devoted to the different strategies for the synthesis of 3-aroylimidazo[1,2-a]pyridines in recent years (2016–2022) using homogeneous or heterogeneous catalysts. The first part is devoted to methods that use 2-aminopyridine and chalcone as starting reagents, then in the second part another variant that uses 2-aminopyridine and 3-phenylpropiolaldehyde, and finally fewer common methods that use other different reagents. Thus, this review will be of interest to many researchers in the field of organic and medicinal chemistry.

A review of recent synthetic strategies and biological activities of isoxazole

AbstractAmong different heterocyclic compounds, isoxazole and their analogues are very important classes of heterocyclic compounds as they display an extensive range of biological actions. This makes such scaffolds very important structures in the field of medicinal chemistry. From an extensive literature assessment, isoxazole is clinically proven to be very effective as an anti‐bacterial, anti‐fungal, anti‐inflammatory, anti‐cancer, anti‐tubercular, and anti‐neoplastic agent. The different derivatives of isoxazole which exhibits adjustment in their structure have shown a high degree of variety in their medicinal properties which makes evident them as very beneficial in the progress of novel bioactive drugs which show enhanced effectiveness along with minor harmfulness. Structural aspects of isoxazole having aromaticity with weaker nitrogen‐oxygen bonding provide a potential site for the ring cleavage. Thus, this isoxazole ring system allows easier modifications of substituents in their ring structure which consequently make isoxazole very useful intermediates in various synthetic routes of bioactive compounds. Hence, the synthesis and evaluation of isoxazole‐containing molecules with wider therapeutic consequences are always the topic of interest for chemists. Hence, in light of this comprehensive research on isoxazole, it is thought worthwhile to review various pathways for the synthesis of isoxazole analogues and having a broad spectrum of bioactive actions.

Molecular docking studies of tyrosine kinase inhibitors: Exemplified protocol to advance pharmaceutical education in medicinal chemistry

Background: One of the essential goals of pharmacy education is to extend professional learning to pharmacists, pharmacy students and educators. Medicinal chemistry is a major component of this professional learning. Nowadays, computer-aided drug design (CADD) is considered a cornerstone in drug discovery platforms. However, this computational drug design is not crystal-clear to pharmacy students and pharmacists. In this study, a molecular docking process was established to advance pharmaceutical education in the medicinal chemistry field. Method: CADD is available in the syllabus of Iraqi pharmacy schools however the software packages are not available for the students to practice the docking process. Five different compounds were designed and docked by employing the Genetic Optimisation of Ligand Docking (GOLD) software and the scores were recorded. Results: Pharmacy students would use this exemplified docking to enhance their understanding of the medicinal chemistry module. Conclusion: This educational docking study was successfully performed to advance the pharmacy education.

Intermolecular hydrogen bonding of alcohols with dinitrobenzene radical anion and dianion: A combined electrochemical and DFT study

Hydrogen bonding is one of the most important inter-molecular interactions in the field of biochemistry and medicinal chemistry. Such non-covalent interactions play a vital role in self-assembly phenomena, chemical structures, material properties and enzymatic catalysis. Herein, we present hydrogen bonding phenomenon in alcohols-dinitrobenzene (DNB) radical anion/dianion systems using electrochemical and computational approaches. First, 1,3-DNB radical anion and dianion were generated through electrochemical method and then hydrogen bonding interactions with aliphatic alcohols in DMSO are studied through cyclic voltammetry (CV). CV results show that the cathodic peak potential of 1,3-Dinitrobenzene in Dimethyl sulfoxide is shifted catholically upon addition of alcohols which represent hydrogen bonding phenomenon. Theoretical investigations are performed to gain deep insight on hydrogen bonding interaction strength in DNB-alcohol systems. H-bonding interaction of all isomers of DNB (1,2-, 1,3-, 1,4-), its corresponding radical anion, and dianion with aliphatic alcohols is studied using density functional calculations. The strength of H-bonding is evaluated both qualitatively and quantitatively using interaction energies, vibrational and electronic spectroscopic analysis. Understanding of these interactions will be helpful in gaining insight into biological systems where these interactions play significant role.

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery.

The concept of bioisosterism and the implementation of bioisosteric replacement is fundamental to medicinal chemistry. The exploration of bioisosteres is often used to probe key structural features of candidate pharmacophores and enhance pharmacokinetic properties. As the understanding of bioisosterism has evolved, capabilities to undertake more ambitious bioisosteric replacements have emerged. Scaffold hopping is a broadly used term in the literature referring to a variety of different bioisosteric replacement strategies, ranging from simple heterocyclic replacements to topological structural overhauls. In this work, we have highlighted recent applications of scaffold hopping in the central nervous system drug discovery space. While we have highlighted the benefits of using scaffold hopping approaches in central nervous system drug discovery, these are also widely applicable to other medicinal chemistry fields. We also recommend a shift toward the use of more refined and meaningful terminology within the realm of scaffold hopping.

Synthesis of Some Novel (Z)-3-ethylidene-5,7-dimethylthiochroman- 4-one Derivatives and Study of its Monoamine Oxidases Inhibitory Activity

Background: Chroman-4-one, also known as 2,3-dihydro-1-benzopyran- 4-one, is a heterocyclic compound with a benzene nucleus fused to a 2,3-dihydro-g-pyranone ring. The synthesis of chroman-4-one derivatives is a very appealing aspect in the field of natural and medicinal chemistry. Materials and Methods: The (Z)-3-ethylidene-5,7-dimethylthiochroman- 4-one derivatives were, synthesized and evaluated intended for their Monoamine oxidases (MAO)-A and MAO-B inhibitory activity using in vitro fluorometric technique. The majority of synthetic process to acquire(Z)-3-ethylidene-5,7-dimethylthiochroman-4-one derivatives engage condensation catalyzed by acid or base of a range of derivatives of 5,7-dimethylchroman-4-one and 4,6-dimethylbenzofuran-3(2H)-one with the benzaldehyde. The Z-isomers that resulted were usually obtained by photoisomerization of the synthesized E-isomers. Synthesized molecules structures (S-1 to S-18) were established by IR, NMR, mass and elemental analysis. Results: The in vitro activity of synthesized (Z)-3-ethylidene-5,7- dimethylthiochroman-4-one derivatives against MAO isoform displayed selectivity in the direction of MAO B isoform. The synthesized derivatives S11 of (Z)-3-ethylidene-5,7-dimethylthiochroman-4-one displayed 7.32 μM (IC50) against MAO-B. Conclusion: Weak to moderate electron pumping and withdrawing groups favor selectivity for hMAO-B, whereas strong deactivators render them non-selective for isoforms. Mono-substitution of methoxy groups at the o- and m-positions improves potency while bi-substitution improves potency and selectivity. The active compounds’ ADME predictions revealed that these synthesized compounds may possess drug likeliness confirmed by excellent pharmacokinetic profiles.

Unveiling a family of spiro-β-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates.

The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure–activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.

Synthesis of L-cyclic tetrapeptides by backbone amide activation CyClick strategy

Cyclic tetrapeptides exhibit high cellular permeability and a wide range of biological properties and thus have gained great interest in the field of medicinal chemistry. We synthesized highly strained 12-membered head to tail cyclic peptides with varying reactive amino acids, without oligomerization using the exclusively intramolecular CyClick chemistry. This occurs by a two-step process involving the low-energy formation of a 15 atom-containing cyclic imine, followed by a chemoselective ring contraction of the peptide backbone generating a highly strained 12 atom-containing cyclic tetrapeptide. This reaction exhibited high substrate scope and generated head to tail cyclic tetrapeptides with varying amino acids at the N-terminus, showing chemoselectivity without the need for side group protection.

Synthesis, Characterization and Molecular Docking Studies of Novel Pteridine Derivatives

Pteridines are a group of heterocyclic compounds which contain nitrogen as a major heteroatom and it was aromatic compounds that are attached to the pyrazine and pyrimidine ring family. Pteridine derivatives have focused on a specific place in the medicinal chemistry field. The Pteridine ring is present in several natural compounds such as Pterin, Hemiptera (erythropoietin), Biopterin, Neopterin, Xanthopterin, iso-xanthopterin, etc., which include a few heterocyclic compounds like pyrimidine, pyrazine rings. Some vitamins like folic acid and riboflavin and drugs like methotrexate and triamterene. A pteridine is formed by a condensation process. A pteridine is frequently produced using costly and dangerous chemicals. In order to reduce the cost and consumption of hazardous chemicals, novel pteridine compounds were made by mixing a catalyst with a solvent, primary amines, and phenols. Currently, the primary issue limiting a medicine's ability to effectively treat a disease includes the development of resistance. In this article, we will utilise docking studies to provide a thorough explanation of the synthesis of pteridine derivatives and their antioxidant capabilities.

Synthesis, Characterization, Anti-bacterial and Anti-inflammatory Activities of Bismuth(III) Complexes Based on 5-chloro-2-mercaptobenzothiazole

Bismuth, known as a heavy metal, is excluded from this class due to its low toxicity. Due to this feature, bismuth containing compounds have always been interesting compounds in the field of medicinal chemistry. For this reason, the discovery of new bismuth compounds and the investigation of their biological properties are very important for this field. In this study, three new bismuth(III) compounds formulated as [Bi(L)2X3] (L: 5-chloro-2-mercaptobenzothiazole (ClMBZT); X: Cl, Br, and I) were synthesized for the first time and, the molecular structure of them were elucidated by a series of spectroscopic techniques. Thermal stability and degradation steps of the title compounds were analyzed by Thermogravimetric-Differential Thermal Analysis (TG-DTA). The antibacterial study has been conducted against six strains bacteria, and the results indicated that bismuth(III) compounds generally showed more effective antibacterial activity than free ligand. The anti-inflammatory potential of bismuth(III) compounds was investigated through in vitro lipoxygenase enzyme inhibition studies. The results show that bismuth(III) compounds have higher anti-inflammatory potential than free ligand.

Ultrasonic-Assisted Synthesis of Benzofuran Appended Oxadiazole Molecules as Tyrosinase Inhibitors: Mechanistic Approach through Enzyme Inhibition, Molecular Docking, Chemoinformatics, ADMET and Drug-Likeness Studies.

Furan-oxadiazole structural hybrids belong to the most promising and biologically active classes of oxygen and nitrogen containing five member heterocycles which have expanded therapeutic scope and potential in the fields of pharmacology, medicinal chemistry and pharmaceutics. A novel series 5a–j of benzofuran-oxadiazole molecules incorporating S-alkylated amide linkage have been synthesized using ultrasonic irradiation and screened for bacterial tyrosinase inhibition activity. Most of the synthesized furan-oxadiazole structural motifs exhibited significant tyrosinase inhibition activity in the micromolar range, with one of the derivatives being more potent than the standard drug ascorbic acid. Among the tested compounds, the scaffold 5a displayed more tyrosinase inhibition efficacy IC50 (11 ± 0.25 μM) than the ascorbic acid IC50 (11.5 ± 0.1 μM). Compounds 5b, 5c and 5d efficiently inhibited bacterial tyrosinase with IC50 values in the range of 12.4 ± 0.0–15.5 ± 0.0 μM. The 2-fluorophenylacetamide containing furan-oxadiazole compound 5a may be considered as a potential lead for tyrosinase inhibition with lesser side effects as a skin whitening and malignant melanoma anticancer agent.

Analysis of Biological Activity of Sulfamide Derivatives as Antimicrobial Agents

Sulfamides are significant compounds because of their biological effects on bacteria, fungi, and cancer. The antimicrobial and anticancer properties of sulfamide derivatives have been demonstrated in several microbial strains and cancer cell lines. They have worked mostly in the field of medicinal chemistry. Numerous microbiological pathogens are known to be resistant to the antibacterial effects of sulfamide derivatives. The most significant microorganisms in command of hospital-acquired nosocomial infections include Acinetobacter baumannii (A. baumannii), Methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans (C. albicans), and Candida parapsilosis (C. parapsilosis). Multiple antibiotics can no longer treat these illnesses. Therefore, it is crucial to develop new antimicrobial agents. Three previously made compounds were tested for their antibacterial properties against these pathogens, including 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,1-dimethyl sulfamide (4) and 3-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,1-dimethyl sulfamide (5). Using the disc diffusion method, antimicrobial activity was assessed, and values for the minimum inhibitory concentration (MIC) were calculated for zone formation seen in the tested pathogens. The results of the investigation demonstrated that sulfamide derivatives stopped the growth of bacteria against A. baumannii with zone widths of 7-9 mm, but had no impact on MRSA, C. albicans, and C. parapsilosis. Sulfamide derivatives' MIC values against A. baumannii were discovered to be 3.90 g/ml. These results provide us the ability to evaluate these sulfamide derivatives as potential new antibacterial therapies for A. baumannii.

Recent development of stereoselective C-glycosylation via generation of glycosyl radical

C-glycosylation through the formation of glycosyl radical is a very feasible and expedient approach for making of the C–C anomeric bond. In this light, this review article is covering selected literature from 2000 to 2022 on the synthetic development of C-glycosylation involving the generation of glycosyl radical as a crucial intermediate in a stereoselective fashion. The generation of glycosyl radical is controlled by the reaction method applying to the radical precursor. Those methods are categorized in terms of a key source of an initiator such as metal-free activation of radical precursor, photochemical induced approach, and metal-mediated approach including transition metal-mediated, lanthanide, and non-transition metal-mediated approach with brief mechanistic discussion, and stereochemical outcome of resultant C-glycosides in detail. This brief discussion accumulates the stereoselective synthesis of challenging C-linked building blocks in a more facile way via generation of glycosyl radical and those building blocks have a great role as drugs, inhibitors, glycoconjugates in the field of biological and medicinal chemistry.

PROSPECTS FOR THE CHEMISTRY OF IMIDAZOLE DERIVATIVES (Review)

The problem of creating new effective domestic pharmacological preparations, including the development of the methods for obtaining biologically active substances in compliance with the “green chemistry” principles, are among the priority areas for the development of chemical science. The choice of an initial molecule, which carries the potential of biological activity, is the guarantor of a successful experimental search. Imidazole derivatives occupy a unique place in the medicinal chemistry. An imidazole cycle is part of the natural compounds such as histamine, biotin, some alkaloids and nucleic acids, and is a structural fragment of medicinal preparations. The goalof the present review is to analyze the publications on the chemistry of imidazole derivatives with an emphasis on the methods of obtaining biologically active and other practically useful molecules with an obligatory imidazole cycle. The objects of the study:imidazole derivatives. The examples of the routes of synthesizing imidazole derivatives, as well as the compounds of interest for the medicinal chemistry, agriculture, and other fields, which have been published in the scientific and technical literature since 2000, have been presented. Conclusion.The studies in the field of searching for new highly effective preparations among imidazole derivatives are relevant and promising. The most important stage in this search is the directed synthesis of the substances with the specified, practically useful properties. The range of new practically useful substances in the series of imidazole derivatives has been significantly expanded and replenished thanks to the modern modifications of the classical methods of their obtaining.

Machine Learning-Based Virtual Screening for the Identification of Cdk5 Inhibitors.

Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field. In this context, we employed a machine learning-based virtual screening protocol with subsequent molecular docking, molecular dynamics simulations and binding free energy evaluations. Our virtual screening studies resulted in the identification of two novel Cdk5 inhibitors, highlighting an experimental hit rate of 50% and thus validating the reliability of the in silico workflow. Both identified ligands, compounds CPD1 and CPD4, showed a promising enzyme inhibitory activity and CPD1 also demonstrated a remarkable antiproliferative activity in ovarian and colon cancer cells. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent Cdk5 inhibitors.