Scaffolds In Medicinal Chemistry Research Articles

A review on synthesis of coumarin derived Schiff’s base metal complexes and their control over E. coli bacterium

Nowadays, the dilemma of drug resistance to antibacterial strains is of huge concern. Among the bacteria, Escherchia coli (E. coli) is the major pathogen, which is found in human and other animals. It is responsible for variety of severe diseases. A variety of commonly used antibiotics such as amoxicillin, gentamycin, etc and fluid replacement method are the suggested treatments for the infections caused by E. coli. In a study, it was established that the metal-based heterocyclic drugs demonstrated a different mode of action compared to the commonly used heterocyclic antibacterial drugs. Coumarin, an oxaheterocycle, is a privileged scaffold in medicinal chemistry. Metal complexes of coumarin-derived Schiff’s bases exhibit a broad range of pharmacological activities. Therefore, in the present review article, we have focused on the synthesis of metal complexes of coumarin derived Schiff’s bases as well as their respective Schiff’s base ligands and their antibacterial activities against the gram-negative bacterium E. coli.

An experimental and computational investigation of the cyclopentene-containing peptide-derived compounds: focus on pseudo-cyclic motifs via intramolecular interactions.

Conformational flexibility is one of the main disadvantages of peptide-based compounds. We focus on their molecular 'chameleonicity' related to forming pseudo-cyclic motifs via modulation of weak intramolecular interactions. It is an appealing strategy for controlling equilibrium between the polar open and the nonpolar closed conformations. Within this context, we report here the crystal structure of the (R)-(2-tert-butoxycarbonyl)amino-1-oxo-3-phenyl)propyl)-1-cyclopentene (1), synthesis of which in high yield was achieved by a facile multi-step protocol. Our Cambridge Structural Database (CSD) overview for the peptide-based crystals revealed the exclusivity of this compound from the viewpoint of the unusual pseudo-bicyclic system via C-H…O and C-O…π interactions, in which cyclopentene shields the amide bond. Notably, cyclopentene as a bioisostere of proline is an appealing scaffold in medicinal chemistry. An extensive combined experimental and computational study provided more profound insight into the supramolecular landscape of 1 with respect to similar derivatives deposited in the CSD, including the tendency of cyclopentene for the generation of pseudo-cyclic motifs through weak H-bonding and π-based intramolecular interactions. These weak interactions have been examined by either the quantum theory of 'atoms-in-molecules' (QTAIM) or complex Hirshfeld surface methodology, including enrichment ratios, molecular electrostatic potential surfaces and energy frameworks. In all analysed crystals, all types of H-bonded motifs involving cyclopentene are formed at all levels of supramolecular architecture. A library of cyclopentene-based H-bonding synthons is provided. A molecular docking study depicted vital interactions of cyclopentene with key amino acid residues inside the active sites of two prominent protein kinases, uncovering the therapeutic potential of 1 against breast cancer. To a large extent, dispersion forces have significance in stabilizing the supramolecular structure of both ligand and bio-complex ligand-protein. Finally, the satisfactory in silico bio-pharmacokinetic profile of 1 related to drug-likeness and blood-brain barrier permeation was also revealed.

A Sonochemical and Mechanochemical One-Pot Multicomponent/Click Coupling Strategy for the Sustainable Synthesis of Bis-Heterocyclic Drug Scaffolds.

Bis-heterocycles were synthesized via a consecutive one-pot process by a Groebke-Blackburn-Bienaymé reaction (GBB-3CR) followed by Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) assisted by alternative sustainable energies (ASE) such as ultrasonic and mechanical. These efficient and convergent strategies allowed the in situ generation of complex azides functionalized with imidazo[1,2-a]pyridines (IMPs), which was used as a synthetic platform. The target molecules contain two privileged scaffolds in medicinal chemistry: IMPs and the heterocyclic bioisostere of trans-amide bond, the 1,4-disubstituted 1H-1,2,3-triazoles (1,4-DS-1,2,3-Ts).

A Review on Synthetic Thiazole Derivatives as an Antimalarial Agent.

Thiazole is a widely studied core structure in heterocyclic chemistry and has proven to be a valuable scaffold in medicinal chemistry. The presence of thiazole in both naturally occurring and synthetic pharmacologically active compounds demonstrates the adaptability of these derivatives. The current study attempted to review and compile the contributions of numerous researchers over the last 20 years to the medicinal importance of these scaffolds, with a primary focus on antimalarial activity. The review is based on an extensive search of PubMed, Google Scholar, Elsevier, and other renowned journal sites for a thorough literature survey involving various research and review articles. A comprehensive review of the antimalarial activity of the thiazole scaffold revealed potential therapeutic targets in Plasmodium species. Furthermore, the correlation of structure-activity-relationship (SAR) studies from various articles suggests that the thiazole ring has therapeutic potential. This article intends to point researchers in the right direction for developing potential thiazole-based compounds as antimalarial agents in the future.

Synthesis, characterization and bioactivity of new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives.

Pyridone heterocycles, such as furo[2,3-b]pyridines, have emerged as prominent scaffolds in medicinal chemistry due to their versatile pharmacological properties, including significant anticancer activity. In this study, we successfully synthesized new pyridine-2(H)-one, nicotinonitrile, and furo[2,3-b]pyridine derivatives from chalcones bearing 4-(benzyloxy)phenyl and dichlorothiophenyl subunits to explore their therapeutic potential against breast cancer. By employing a synthetic strategy involving Claisen-Schmidt condensation followed by sequential cyclizations and functional modifications, we synthesized and characterized four compounds (MI-S0, MI-S1, MI-S2, and MI-S3) using various spectroscopic methods, including FT-IR, 1H-NMR, 13C-NMR, DEPT, H,H- and C,H-COSY, and HRMS. The in vitro cytotoxic activity of these compounds was evaluated against two breast cancer cell lines, MCF-7 and MDA-MB-231, and compared with a noncancerous breast cell line, MCF-10A. All compounds exhibited potent cytotoxic activities with minimal selectivity toward normal cells. Molecular docking studies targeting the serine/threonine kinase AKT1, estrogen receptor alpha (ERα), and human epidermal growth factor receptor 2 (HER2) revealed strong binding affinities, suggesting a mechanism involving the disruption of key cellular signaling pathways. These findings underscore the potential of furo[2,3-b]pyridine derivatives as promising candidates for further development into anticancer agents, laying the groundwork for future investigations into their selective therapeutic efficacy and molecular mechanisms of action.

Synthesis of amino juglone derivatives with adjuvant activity against clinical isolated methicillin-resistant staphylococcus aureus strains

1,4-naphthoquinones hydroxyderivatives belong to an important class of natural products and have been known as a favored scaffold in medicinal chemistry due to their multiple biological properties. Juglone is one of the most important 1,4-naphthoquinone extracted from juglandaceae family showing a good antibacterial activity. In this study, we report the synthesis of aminojuglone derivatives through Michael addition reaction using Cerium (III) chloride heptahydrate (CeCl3·7H2O) as catalyst. The synthesized aminojuglone derivatives were evaluated for their antibacterial properties against sensitive, clinical resistant Gram-positive and Gram-negative bacterial strains. Compound 3c showed a good antibacterial activity similar to cloxacillin (2 µg/mL) against the clinically resistant S.aureus. The antibiotic adjuvant activity of compounds was evaluated in combination with three clinically use antibiotics. The combination of compounds 3a, 3b, 3e, 3 h-3 l, 3n and 3o with cloxacillin showed remarkable adjuvant activity against clinically resistant S. aureus (66-fold potentiation of cloxacillin activity). 3e is the only compound consistent with the concept of antibiotic adjuvant, presenting insufficient antibacterial activity (MIC > 128 µg/mL) and potentiate the activity of cloxacillin (66-fold) with synergistic effect. A structural characterization of 3e was carried out for the first time using X-ray diffraction technic. Moreover, compound 3e did not show a cytotoxic activity on sheep red blood cells.

Synthesis, Characterization, Docking Study and Biological Activates of New 3-Aminorhodanine Derivatives

Abstract: Increase in fatalities among cancer patients is one of untreated facts and today cancer remains one of the main health issues. The most common cause of cancer death is lung cancer. Rhodanine has been recognized as a privileged scaffold in medicinal chemistry due to its well-known ability to demonstrate a broad range of biological activities, and most of its derivatives exhibited remarkable anticancer activity in the (μg/mL) concentration range, while causing negligible cytotoxicity to normal cells. New N- and 5- disubstituted aminorhodanine derivatives were synthesized by Schiff base and Knoevenagel condensation reactions over two consecutive steps. Human cancer cells and Hdfn (human dermal fibroblasts isolated from neonatal foreskin) cells line, were used to evaluate the synthesized compounds’ activity by MTT assay. The new compounds revealed higher anticancer activity against A549 lung cells cancer when compared with reference drug Erlotinib (anticancer drug) and determined no toxicity or safety on normal cell. Among the tested compounds, 2b2 compound show potent anticancer activity which have IC50 about (55.8 μg/mL).

Significance of Chalcone Scaffolds in Medicinal Chemistry.

Chalcone is a simple naturally occurring α,β-unsaturated ketone with biological importance, which can also be easily synthesized in laboratories by reaction between two aromatic scaffolds. In plants, chalcones occur as polyphenolic compounds of different frameworks which are bioactive molecules that have been in traditional medicinal practice for many years. Chalcone-based lead molecules have been developed, possessing varied potentials such as antimicrobial, antiviral, anti-inflammatory, anticancer, anti-oxidant, antidiabetic, antihyperurecemic, and anti-ulcer effects. Chalcones contribute considerable fragments to give important heterocyclic molecules with therapeutic utilities targeting various diseases. These characteristic features have made chalcone a topic of interest among researchers and have attracted investigations into this widely applicable structure. This review highlights the extensive exploration carried out on the synthesis, biotransformations, chemical reactions, hybridization, and pharmacological potentials of chalcones, and aims to provide an extensive, thorough, and critical review of their importance, with emphasis on their properties, chemistry, and biomedical applications to boost future investigations into this potential scaffold in medicinal chemistry.

Synthesis and In Silico Studies of Quinazolinones as PARP-1 Inhibitors.

Cancer is a leading threat to humankind, accounting for nearly one million deaths in 2018, and the expected number of cancer-related deaths in 2040 is more than 16 million. The most common causes of cancer deaths are lung, colorectal, stomach, liver and breast cancer, while the highest number of new cancer cases belong to lung, breast, colorectal, prostate, stomach and liver cancer. PARP-1 is an enzyme that plays an important role in DNA repair, cell propagation/survival and death due to its influence on numerous biological processes. Quinazolinones represent an important scaffold in medicinal chemistry and have a broad spectrum of biological activities. In this study, we have synthesized quinazolinones by reaction of 2-aminobenzamide and substituted aldehydes. Molecular docking studies of synthesized compounds were performed for their PARP-1 binding affinities using Schrodinger 2016 software. In silico ADME studies were also performed for the synthesized compounds using the QikProp tool of Schrodinger software. Results of molecular docking studies indicated that synthesized quinazolinones had a good affinity towards active site of PARP-1 and compound 4 had the best docking score (-10.343). Results of ADME studies indicated the drug-like properties of synthesized compounds, which make them suitable drug candidates. All the synthesized compounds have a better docking score than niraparib (-9.05). Further, the synthesized compounds have a favorable ADME profile. Therefore, they may serve as important leads in discovering PARP-1 inhibitors.

A ChemoEnzymatic Approach for the Preparation of “Linear‐Shaped” Diaryl Pyrazines as Potential Antiprotozoal Agents

AbstractNitrogenous heterocyclic rings are present in a wide range of drugs, natural compounds, and fine chemicals and are considered privileged scaffolds in medicinal chemistry. Seeking novel anti‐protozoal drugs acting on new targets or by novel mechanisms of action, we focused on a preliminary evaluation of the potential of “linear‐shaped” diaryl pyrazines. To this purpose, a two‐enzyme chemoenzymatic synthesis of this heteroaromatic core was carried out. Specifically, starting from simple, commercially available aromatic aldehydes, the target pyrazines were obtained through a sequence of biocatalytic benzoin condensation, chemical oxidation and a transaminase‐mediated tandem process of transamination and cyclization. The profiles of the compounds as antiprotozoal agents were evaluated in vitro against parasites cultures of the Leishmania and Plasmodium genera and using the human cell line HepG2.

Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

Fluorescent 2-carbonyl carbazole ketones: Photophysical properties, molecular structure and selective detection of Fe3+ ion

Owing to the diverse implication of carbazole scaffolds in medicinal chemistry, photoelectronic materials and chromophores, the molecules containing the carbazole motif have attracted significant attention over the years. In this work, the vibronic contributions to carbazole structures could facilely change the solvatochromic effect, absorption wavelength, emission wavelength, and Stokes shifts of six 2-carbonyl carbazole ketones fluorophores. Among them, the structure of 1-(1-methyl-9H-carbazol-2-yl)ethanone (3a) were confirmed from single crystal XRD studies. The ratiometric detection of Fe(III) ion of 2-carbonyl carbazole ketone 3a were investigated. Furthermore, it was speculated that chemosensor 3a toward the recognition of Fe3+ cation was dependent on its rigid structure and good coplanarity of the conjugated system, strong intramolecular charge-transfer of 3a.

Review on advancements of pyranopyrazole: synthetic routes and their medicinal applications.

Pyranopyrazoles are among the most distinguished, biologically potent, and exciting scaffolds in medicinal chemistry and drug discovery. Synthesis and design of pyranopyrazoles using functional modifications via multicomponent reactions (MCRs) are thoroughly found in synthetic protocols by forming new C-C, C-N, and C-O bonds. This review aims to focus on the biological importance of pyranopyrazoles as well as on a diverse synthetic approach for their synthesis using various catalytic systems such as acid-catalyzed, base-catalyzed, ionic liquids and green media-catalyzed, nano-particle-catalyzed, metal oxide-supported catalysts, and silica-supported catalysts. In this review, we have summarized data on the advancements in synthesizing pyranopyrazole from the last two decades to the mid-2023 and research papers describing the importance of these scaffolds. This review will be significant for synthetic organic chemists and researchers working in organic chemistry.

The design, synthesis, and biological evaluation of 5,6,7,8-tetrahydropteridines as anti-inflammatory compounds.

The NLRP3 inflammasome is implicated in the pathogenesis of a wide array of inflammatory diseases including cancer, type II diabetes, atherosclerosis, gout, and neurodegenerative disease. Research has shown that Bruton's tyrosine kinase (BTK) is a critical regulator of the NLRP3 inflammasome and that the pharmacological inhibition of BTK using the FDA-approved inhibitor ibrutinib diminishes NLRP3-dependent inflammatory response. Herein, we describe our pursuit towards novel anti-inflammatory compounds using a scaffold-hopping approach. In our drug discovery efforts, we identified 5,6,7,8-tetrahydropteridines as underutilized scaffolds in medicinal chemistry. We report the synthesis of 5,6,7,8-tetrahydropteridines with potential as anti-inflammatory compounds.

Recent advances in the synthesis and medicinal perspective of pyrazole-based α-amylase inhibitors as antidiabetic agents.

Diabetes is a serioushealth threat across the globe, claiming millions of lives worldwide. Among the various strategies employed, inhibition of α-amylase is a therapeutic protocol for the management ofType 2 diabetes mellitus. α-Amylase is a crucial enzyme involved in the breakdown of dietary starch into simpler units. However, the clinically used α-amylase inhibitors have various drawbacks. Therefore, design and development of novel α-amylase inhibitors have gained significant attention. The pyrazole motif has been identified as a versatile scaffold in medicinal chemistry, and recent studies have led to the identification of various pyrazole-based α-amylase inhibitors. This review compiles therapeutic implications of pyrazole-appended α-amylase inhibitors; their synthesis, biological activities, structure-activity relationships and molecular docking studies are discussed.

LED-induced Ru-photoredox Pd-catalyzed C-H arylation of (6-phenylpyridin-2-yl)pyrimidines and heteroaryl counterparts.

N-heterocycles are essential building blocks and scaffolds in medicinal chemistry. A Pd-catalyzed, Ru-photoredox-mediated C-H arylation is applied herein, for converting a series of functionality-inclusive (6-phenylpyridin-2-yl)pyrimidines to single arylated derivatives, using phenyldiazonium tetrafluoroborate as aryl source. This green chemistry-compliant transformation is induced by LED light. The drug-like modular substrates are constructed via combination of Biginelli multi-component condensation and Suzuki C-C cross-coupling, in order to strategically install, adjacent to the Ph-ring intended to undergo C-H arylation, a (6-pyridin-2-yl)pyrimidine that plays the role of a chelating directing moiety for the C-H arylation catalyst. The scope has been demonstrated on a series of 26 substrates, comprising diverse Ph-ring substituents and substitution patterns, as well as with 13 different aryl donors. Substrates in which the Ph-ring (arylation acceptor) was replaced by an electron-rich heteroaryl counterpart (2-/3-thiophene or -benzofuran) have also been examined and found to undergo arylation regioselectively. End-product conformations afford interesting motifs for occupying 3D chemical space, as implied by single-crystal X-ray diffraction, which has allowed the elucidation of six structures of aryl derivatives and one of an unprecedented pyrimidine-pyridine-benzofuran carbopalladated complex, believed to be a C-H activation derivative.

Electrochemical promoted three-component reaction to unsymmetric thiosulfonates.

Compounds comprising S-S bonds serve as significant pharmacological scaffolds in medicinal chemistry and natural products. We have devised an efficient electrochemical method for the construction of asymmetric disulfide bonds, leading to the synthesis of unsymmetric thiosulfonates. Compared with existing synthesis methods, our work not only avoids the use of metals and oxidants, but also realizes the operation of a one-pot three-component method, which makes this strategy extremely attractive.

Insight into Indole‐Based Heterocyclic Scaffolds: A Medicinal Chemistry Perspective

AbstractThe importance of indole‐based heterocycle scaffolds in medicinal chemistry has increased as a result of their significant pharmacological and biological characteristics. These compounds′ importance in the discovery and creation of cutting‐edge medications to treat a variety of diseases is an instance of their worth. The current study highlights the numerous methods available to create different indole‐based heterocycle scaffolds and their favourable medical uses with the literature that has been published up to 2023.

Synthesis and in Silico Studies of Some New 1,2,3-Triazolyltetrazole Bearing Indazole Derivatives as Potent Antimicrobial Agents.

1,2,3-Triazole and tetrazole derivatives bearing pyrrolidines are found to exhibit notable biological activity and have become useful scaffolds in medicinal chemistry for application in lead discovery and optimization. Novel indazole bearing 1,2,3-triazolyltetrazoles were designed as potential antimicrobial candidates. The structure of duel heterocyclics was validated by a spectroscopic technique of infrared (IR), nuclear magnetic resonance (1 H and 13 C NMR), and mass spectral data. Compounds 4b, 4c, 4d, and 4h were found to have a stronger antibacterial effect against Gram-positive (S. aureus, B. subtilis, M. Luteus) and Gram-negative (E. coli, P. aeruginosa) microorganisms with MICs ranging from 5±0.03-18±0.02 μM, respectively. Moreover, scaffolds 4a, 4h showed potent antifungal activity against A. flavus, M. gypsuem strains with MIC values of 10±0.02, 11±0.01 μM, which are similar activity that of the standard Itraconazole (MIC=8±0.02, 10±0.01 μM). The binding mode for compound 4 inside the catalytic pocket of S. aureus complexed with nicotinamide adenine dinucleotide phosphate and trimethoprim and produced a network of hydrophobic and hydrophilic interactions (3FRE). From in silico results, 4b demonstrated highly stable hydrogen binding amino acids Leu62(X) [N18…O, 2.47 Å], Arg44(X) [N17…N, 3.11 Å], Thr96(X) [N10…OG1, 3.05 Å], Gly94(X) [F7…N, 2.82 Å], and Gly43(X) [F7…N, 2.90 Å], which are plays a crucial role in ensuring efficient binding of the ligand in a crystal structure of antibacterial receptor. Furthermore, the physicochemical and ADME filtration molecular properties, estimation of toxicity, and bioactivity scores of these novel scaffolds were evaluated by using SwissADME and ADMETlab2.0 online protocols. Thus, the significant antimicrobial activity of indazole linked to duel heterocyclic compounds can be used for development of new antimicrobial agents with further modifications.

CsPbBr3 Perovskite Nanocrystals for Photocatalytic [3+2] Cycloaddition.

Visible-light-induced halide-exchange between halide perovskite and organohalide solvents has been studied in which photoinduced electron transfer from CsPbBr3 nanocrystals (NCs) to dihalomethane solvent molecules produces halide anions via reductive dissociation, followed by a spontaneous anion-exchange. Photogenerated holes in this process are less focused. Here, for CsPbBr3 in dibromomethane (DBM), we discover that Br radical (Br⋅) is a key intermediate resulting from the hole oxidation. We successfully trapped Br⋅ with reported methods and found that Br⋅ is continuously generated in DBM under visible light irradiation, hence imperative for catalytic reaction design. Continuous Br⋅ formation within this halide-exchange process is active for photocatalytic [3+2] cycloaddition for vinylcyclopentane synthesis, a privileged scaffold in medicinal chemistry, with good yield and rationalized diastereoselectivity. The NC photocatalyst is highly recyclable due to Br-based self-healing, leading to a particularly economic and neat heterogeneous reaction where the solvent DBM also acts as a co-catalyst in perovskite photocatalysis. Halide perovskites, notable for efficient solar energy conversion, are demonstrated as exceptional photocatalysts for Br radical-mediated [3+2] cycloaddition. We envisage such perovskite-induced Br radical strategy may serve as a powerful chemical tool for developing valuable halogen radical-involved reactions.