Design, synthesis, antimicrobial activity, DFT, and molecular docking studies of pyridine-pyrazole-based dihydro-1,3,4-oxadiazoles against various bacterial and fungal targets.

Antimicrobial resistance which is increasing at an alarming rate is a severe public health issue worldwide. Hence, the development of novel antibiotics is an urgent need as microbes have developed resistance against available antibiotics. In search of novel antimicrobial agents, a convenient route for the preparation of substituted 3-(1-phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)-1-(2-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)prop-2-en-1-ones (6a-6o) has been adopted by using pyridine-3-carbohydrazide and various aromatic aldehydes. The newly synthesized compounds were characterized by using various spectral techniques, for example, IR, 1 H NMR, 13 C NMR, and mass spectroscopy. Synthesized hybrids were studied for in vitro antimicrobial potency against various bacterial and fungal strains. Antibacterial results revealed that compounds 6e, 6h, 6i, 6l, and 6m were found to be most active against bacterial strains as they showed minimum inhibitory concentration (MIC) value of 62.5 µg/mL while compounds 6d, 6e, and 6h showed MIC value of 200 µg/mL against Candida albicans. The quantum parameters that relate to the bioavailability of the compounds were computed, followed by docking with different bacterial and fungal targets like sortase A, dihydrofolate reductase, thymidylate kinase, gyrase B, sterol 14-alpha demethylase. The experimental and computational results are in good agreement.

Design and synthesis of some novel hybrid molecules based on 4-thiazolidinone bearing pyridine-pyrazole scaffolds: molecular docking and molecular dynamics simulations of its major constituent onto DNA gyrase inhibition.

Due to multidrug resistance, microbial infections have become significant on a global level. As infections caused by several resistant bacteria and fungi severely harm mankind, scientists have developed new antibiotics to combat these infections. In order to develop novel antimicrobial agents, a series of 4-thiazolidinone-based 5-arylidene hybrids (5a-o) have been designed and synthesized to evaluate their antibacterial and antifungal activities. For the determination of the structure of a novel synthesized hybrid, various spectral techniques, e.g., IR, 1H NMR, 13C NMR, and Mass spectroscopy, were used. Two bacterial gram-negative (Escherichia coli and Pseudomonas aeruginosa), two gram-positive strains (Staphylococcus aureus and Streptococcus pyogenes), and one fungal strain (Candida albicans) were used to evaluate antimicrobial activity. Compounds 5c, 5g, and 5i were effective due to their MIC values of 62.5 µg/mL against tested bacterial strains (S. pyogenes (5c), P. aeruginosa (5g), and E. coli (5i), respectively.) and 250 µg/mL against C. albicans fungal strains, respectively. Additionally, molecular docking and 100 ns molecular dynamic simulations were carried out to investigate the stability of molecular contacts and to establish how the newly synthesized inhibitors fit together in the most stable conformations.

Oxadiazole: A highly versatile scaffold in drug discovery.

As a pharmacologically important heterocycle, oxadiazole paved the way to combat the problem associated with the confluence of many commercially available drugs with different pharmacological profiles. The present review focuses on the potential applications of five-membered heterocyclic oxadiazole derivatives, especially 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, as therapeutic agents. Designing new hybrid molecules containing the oxadiazole moiety is a better solution for the development of new drug molecules. The designed molecules may accumulate a biological profile better than those of the drugs currently available on the market. The present review will guide the way for researchers in the field of medicinal chemistry to design new biologically active molecules based on the oxadiazole nucleus. Antitubercular, antimalarial, anti-inflammatory, anti-HIV, antibacterial, and anticancer activities of various oxadiazoles have been reviewed extensively here.

Conventional and microwave-assisted organic synthesis of novel antimycobacterial agents bearing furan and pyridine hybrids.

Drug resistance in tuberculosis poses a serious threat to humanity because currently available antitubercular drugs are ineffective against Mycobacterium tuberculosis (M. tuberculosis). As a result, the approval of Bedaquiline and Delamanid for the treatment of drug-resistant tuberculosis was accelerated. Still, there is an urgent need to search for new antitubercular drugs with novel mechanisms of action (MoA). Due to this, we have designed a synthetic strategy by utilizing microwave-assisted organic synthesis. We have compared our method with the conventional procedure, and the data show that our procedure is more effective in the preparation of title compounds. A unique series of 1-(2-(furan-2-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)-prop-2-en-1-ones (5a-o) was synthesized utilizing conventional and microwave-assisted techniques. Synthetic compounds were investigated for antitubercular activity against Mycobacterium TB H37 Ra and Mycobacterium bovis (M. bovis). Compound 5b was reported to be the most effective against M. tuberculosis H37 Ra (97.69 percent inhibition at 30 µg/ml) and M. bovis (97.09 percent inhibition at 30 µg/ml). An in silico binding affinity study of mycobacterial enoyl-acyl carrier protein reductase (InhA) reveals the binding mechanism and thermodynamic interactions that determine these molecule's binding affinity. Compound 5b had a high glide score of -8.991 and low glide energy of -49.893 kcal/mol.

Synthesis, molecular docking, DFT study, and in vitro antimicrobial activity of some 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives.

The evolution of microbial resistance necessitates the development of new antimicrobial drugs that are more effective than those currently on the market. To address this problem, we have prepared a series of novel 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives via Hantzsch reaction using nine different compounds containing active methylene group. IR, NMR, and mass spectra were used to determine the structures. Using ampicillin and griseofulvin as standards, the titled compounds were investigated for their antibacterial activity against different bacteria and fungi. Compounds 1f, 1g, 2f, and 2g have the best antibacterial activity against Gram-negative bacteria (minimum inhibitory concentration = 50 µg/ml), while 1f, 1h, 2g, and 2h have high antifungal activity against Candida albicans (minimum inhibitory concentration = 100 µg/ml). To gain a better understanding of the binding process and affinity for the bacterial Staphylococcus epidermidis protein, researchers used molecular docking and molecular mechanics, as well as the generalized Born model and solvent accessibility-based binding free energy. The active compounds 1g, 1h, and 2f have good docking scores of -5.575, -5.949, and -5.234, respectively, whereas compound 2c has the greatest docking score (-6.23). The HOMO-LUMO energy gap and molecular electrostatic potential were used to evaluate the reactivity of promising compounds, which were then associated with antibacterial efficacy.

Synthesis, antitubercular, antimicrobial activities and molecular docking study of quinoline bearing dihydropyrimidines.

In order to develop the antimicrobial and antitubercular agents, we have derived quinoline bearing dihydropyrimidine analogues 5a-o and structures of these compounds were determined by spectroscopic techniques. Further, we have calculated the molecular properties prediction and drug-likeness by Molinspiration property calculation toolkit and MolSoft software, respectively. The most active compound against Mycobacterium tuberculosis (5m, MIC = 0.20 µg/mL) also possessed a maximum drug-likeness model score (0.42). Compounds 5m, 5g and 5k were possessed promising antibacterial activity against tested bacterial species. Compound 5k was the only compound to have eye-catcher antifungal activity. Furthermore, the MTT cytotoxicity results on HeLa cells suggested lower cytotoxicity of biologically active compounds. Supramolecular interactions of the synthesized compounds has been assessed my means of molecular docking studies. Although all the synthesized compounds are showing preferably good interactions with their respective proteins, their binding free energies values suggest that these molecules are preferred for antitubercular activity rather than antimicrobial activity.

In silico molecular docking studies of oxadiazole and pyrimidine bearing heterocyclic compounds as potential antimicrobial agents.

Microbial resistance is a major problem faced by the scientific community. It has created an urgent need to develop antimicrobial agents with novel structures and mechanisms of action. With this aim, a series of novel 1,3,4-oxadiazoles bearing 3,4-dihydropyrimidine heterocyclic motifs 4a-l were designed and synthesized. One-pot Biginelli synthesis is pivotal due to the use of readily available chemicals, shorter reaction time, and ecofriendly synthesis with a good yield. The structures of the synthesized molecules were characterized and confirmed by infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectroscopic techniques. The title compounds were screened against Gram-positive and -negative strains of bacteria and fungi using the Mueller-Hinton broth method. Compound 4d was found to be the most promising against Escherichia coli (12.5 µg/ml), whereas the same compound showed good activity against Staphylococcus aureus at a concentration of 50 µg/ml. Other compounds of the same series, 4c and 4h, displayed moderate activity against Streptococcus pyogenes at a concentration of 50 µg/ml. Furthermore, results of the antifungal activity tests revealed that compound 4i showed promising activity against all the strains of fungi, Candida albicans, Aspergillus niger, and Aspergillus clavatus, at concentrations of 100, 50, and 100 µg/ml, respectively. Molecular docking also showed that these compounds had a significant binding affinity (Glide docking score: -7.74 to -6.531) for DNA gyrase, engaging in a series of bonded and nonbonded interactions with residues lining the active site. The results of molecular docking study validated the experimental findings, thereby providing an initiation mark to optimize this motif using a structure-based drug design approach.

Synthesis and antibacterial and cytotoxic activities of new N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety.

Two new series of N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety (5a-j and 7a-j) were synthesized and assessed in vitro for their efficacy as antibacterial agents against gram-positive and gram-negative bacterial strains. Among the tested compounds, 7b, 7c, 7i, and 7j were found to be active against gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes) with minimum inhibitory concentration (MIC) values in the range of 6.25-25 µg/mL, and some compounds were also tested against methicillin-resistant S. aureus (MRSA). Compounds 7c and 7j inhibited the growth of MRSA at MIC values of 6.25 and 12.5 µg/mL, respectively. The influence of the lipophilicity (C log P) on the biological profile (MIC) of the prepared products was also discussed. From the standpoint of structure-activity relationship studies, it was observed that the lipophilic profiles of the compounds were crucial for their antibacterial activities. Further, the results of the MTT cytotoxicity studies on a human cervical cancer cell line (HeLa) and a mouse embryonic fibroblast cell line (NIH 3T3) suggested that compounds 7b, 7c, 7i, and 7j were endowed with low levels of cytotoxicity.

Design and Synthesis of the Linezolid Bioisosteres to Resolve the Serotonergic Toxicity Associated with Linezolid.

Serotonergic toxicity due to MAO enzyme inhibition is a significant concern when using linezolid to treat MDR-TB. To address this issue, we designed linezolid bioisosteres with a modified acetamidomethyl side chain at the C-5 position of the oxazolidine ring to balance activity and reduce toxicity. Among these bioisosteres, R7 emerged as a promising candidate, demonstrating greater effectiveness against M. tuberculosis (Mtb) H37Rv cells with an MIC of 2.01 µM compared to linezolid (MIC = 2.31 µM). Bioisostere R7 also exhibited remarkable activity (MIC50) against drug-resistant Mtb clinical isolates, with values of 0.14 µM (INHR, inhA+), 0.53 µM (INHR, katG+), 0.24 µM (RIFR, rpoB+), and 0.92 µM (INHR INHR, MDR). Importantly, it was >6.52 times less toxic as compared to the linezolid toward the MAO-A and >64 times toward the MAO-B enzyme, signifying a substantial improvement in its drug safety profile.

Synthesis of pyrazole encompassing 2-pyridone derivatives as antibacterial agents.

A series of novel compounds 6-amino-1-((1,3-diphenyl-1H-pyrazole-4-yl)methyleneamino)-4-(aryl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (4a-t) were synthesized and characterized by IR, (1)H NMR, (13)C NMR and mass spectral data. These compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus, Streptococcus pyogenes (Gram positive), Escherichia coli, Pseudomonas aeruginosa (Gram negative) by serial broth dilution and cytotoxic activity (NIH 3T3 & HeLa) by MTT assay. The results indicated that compounds 4g, 4i, 4m, 4o, 4r and 4t exhibit potent antibacterial activity against bacterial strains at non-cytotoxic concentrations.

Benzothiazole Clubbed Imidazolone Derivatives: Synthesis, Molecular Docking, DFT Studies, and Antimicrobial Studies.

AIM: This study aims to synthesize antimicrobial agents and their molecular docking, and DFT studies of benzothiazole-imidazolone scaffolds. BACKGROUND: Benzothiazole and imidazolone analogues are of interest due to their potential activity against microbial infections. In search of suitable antimicrobial compounds, we report here the synthesis, characterization, and biological activities of benzothiazole and imidazolone analogues (4a-l). OBJECTIVE: The benzothiazole clubbed imidazolone motifs were synthesized, characterized, and screened for their antimicrobial activity. Molecular docking was carried out for the development of antimicrobial agents based on the results of biological activity obtained. METHODS: We have synthesized a new series of benzothiazole-clubbed imidazolone hybrids by using multi-step reactions in the search for antimicrobial agents (4a-l). The structures were determined by 1H NMR, 13C NMR, IR, and mass spectroscopy techniques. Moreover, synthesized compounds were evaluated for their antimicrobial activity by using a Serial Broth Dilution method. In addition, molecular electrostatic potential, geometric optimization, and molecular reactivity analyses (HOMO-LUMO) of 4c, which is one of the compounds with the highest antibacterial activity, were performed. RESULTS: The in vitro antimicrobial activity was evaluated against pathogenic strains. Among them, compounds 4c showed the most potent biological activity against Gram-negative bacteria, E. coli with MIC values of 50 µg/mL, and compound 4c active against A. clavatus with MIC values of 100 µg/mL. Active compound 4c HUMO-LUMO energies, molecular electrostatic potential analysis, and geometric optimization parameters were calculated with a 6-31G ** base set using DFT/B3LYP theory, and the results were displayed. Molecular docking studies were performed on E. coli DNA Gyrase B to understand the binding interaction of compound 4c, and it was observed that compound 4c interacted with Arg76 amino acid of the active site through hydrophobic interaction. CONCLUSION: Benzothiazole-clubbed imidazolone hybrids (4a-l) indicated promising antimicrobial activity. Among them, compounds 4b (MIC=50 µg/mL C. albicans), 4c (MIC=50 µg/mL, E. coli), 4e (MIC= 100 µg/mL, A. niger), and 4g (MIC= 50 µg/mL, S. pyogenes) with electronwithdrawing bromo, chloro, and fluoro group at the para position of the phenyl ring on benzothiazole-imidazolone hybrids indicated remarkable potency compared to the standard drug. The geometric optimization, molecular reactivity, and MESP analyses of 4c were calculated with the B3LYP/6-31G ** base set and ΔE = ELUMO-EHOMO, which was found to be - 0.12096 eV. In addition, the binding affinity scores correlated well with the in vitro antimicrobial activity (4c), while their binding modes proposed the involvement of steric, electrostatic, and hydrogen- bonding interactions with the active site.

Synthesis, Antifungal Ergosterol Inhibition, Antibiofilm Activities, and Molecular Docking on ß-Tubulin and Sterol 14-Alpha Demethylase along with DFT-Based Quantum Mechanical Calculation of Pyrazole Containing Fused Pyridine-Pyrimidine Derivatives.

Multidrug-resistant fungal infections have become much more common in recent years, especially in immune-compromised patients. Therefore, researchers and pharmaceutical professionals have focused on the development of novel antifungal agents that can tackle the problem of resistance. In continuation to this, a novel series of pyrazole-bearing pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives (4a-4o) have been developed. These compounds have been screened against Candida albicans, Aspergillus niger, and Aspergillus clavatus. The synthesized compounds were characterized by well-known spectroscopic techniques, i.e., IR, 1H NMR, 13C NMR, and mass spectrometry. In vitro antifungal results revealed that compound 4n showed activity against C. albicans having MIC value of 200 µg/mL. To know the plausible mode of action, the active derivatives were screened for anti-biofilm and ergosterol biosynthesis inhibition activities. The compounds 4h, 4j, 4k, and 4n showed greater ergosterol biosynthesis inhibition than the control DMSO. To comprehend how molecules interact with the receptor, studies of molecular docking of 4k and 4n have been performed on the homology-modeled protein of ß-tubulin. The molecular docking revealed that the active compounds 4h, 4j, 4k, 4l, and 4n interacting with the active site amino acid of sterol 14-alpha demethylase (PDB ID: 5v5z) indicate one of the possible modes of action of ergosterol inhibition activity. The synthesized compounds 4c, 4e, 4h, 4i, 4j, 4k, 4l, and 4n inhibited biofilm formation and possessed the potential for anti-biofilm activity. DFT-based quantum mechanical calculations were carried out to optimize, predict, and compare the vibration modes of the molecule 4a.

Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis.

Serotogenic toxicity is a major hurdle associated with Linezolid in the treatment of drug-resistant tuberculosis (TB) due to the inhibition of monoamine oxidase (MAO) enzymes. Azole compounds demonstrate structural similarities to the recognized anti-TB drug Linezolid, making them intriguing candidates for repurposing. Therefore, we have repurposed azoles (Posaconazole, Itraconazole, Miconazole, and Clotrimazole) for the treatment of drug-resistant TB with the anticipation of their selectivity in sparing the MAO enzyme. The results of repurposing revealed that Clotrimazole showed equipotent activity against the Mycobacterium tuberculosis (Mtb) H37Rv strain compared to Linezolid, with a minimal inhibitory concentration (MIC) of 2.26 µM. Additionally, Clotrimazole exhibited reasonable MIC50 values of 0.17 µM, 1.72 µM, 1.53 µM, and 5.07 µM against the inhA promoter+, katG+, rpoB+, and MDR clinical Mtb isolates, respectively, compared to Linezolid. Clotrimazole also exhibited 3.90-fold less inhibition of MAO-A and 50.35-fold less inhibition of MAO-B compared to Linezolid, suggesting a reduced serotonergic toxicity burden.

Synthesis and characterization of some new quinoline based derivatives endowed with broad spectrum antimicrobial potency.

The synthesis of a novel series of 2-(5-(2-chloro-6-fluoroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones (4a-l) and N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholinoacetamides (7a-l) are described in the present paper. The chemical structures of compounds have been elucidated by IR, (1)H NMR, (13)C NMR and mass spectral data. Antimicrobial activity was measured against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Evaluation of antimicrobial activity showed that several compounds exhibited greater activity than reference drugs and thus could be promising new lead molecules.

Synthesis, Molecular Modeling Study, and Quantum-Chemical-Based Investigations of Isoindoline-1,3-diones as Antimycobacterial Agents.

The condensation of phthalic anhydride afforded structurally modified isoindoline-1,3-dione derivatives with selected amino-containing compounds. The title compounds (2-30) have been characterized by thin-layer chromatography (TLC), infrared spectroscopy, 1H and 13C NMR spectroscopy, and mass spectroscopy. All of the compounds were assessed for their antimycobacterial activity toward the H37Rv strain by a dual read-out assay method. Among the synthesized compounds, compound 27 possessed a significant IC50 of 18 µM, making it the most potent compound of the series. The InhA inhibitory (IC50) activity of compound 27 was 8.65 µM in comparison to Triclosan (1.32 µM). Computational studies like density functional theory (DFT) study, molecular docking, and dynamic simulation studies illustrated the reactivity and stability of the synthesized compounds as InhA inhibitors. A quantum-mechanics-based DFT study was carried out to investigate the molecular and electronic properties, reactivities, and nature of bonding present in the synthesized compounds and theoretical vibrational (IR) and isotropic value (1H and 13C NMR) calculations.

Conventional and Microwave-Assisted Synthesis, Antitubercular Activity, and Molecular Docking Studies of Pyrazole and Oxadiazole Hybrids.

Microwave-assisted organic reaction enhancement (MORE) has become more important in synthetic organic chemistry for efficient resource utilization. In this study, we synthesized bioactive compounds using both traditional and microwave methods. Microwave-assisted synthesis takes less time and produces higher yields and quality than conventional approaches. We reported the synthesis of N'-(1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene) substituted hydrazides (4a-t). We also tested them against two strains: M. tuberculosis H37Ra and M. bovis BCG. Against M. tuberculosis H37Ra, the compounds 4e, 4h, 4k, 4p, and 4s were the most effective. Compounds 4f, 4g, and 4s showed significant activity against M. bovis BCG. The structures of newly synthesized molecules were determined using spectral methods. Furthermore, molecular docking investigations into the active site of mycobacterial InhA yielded well-clustered solutions for these compounds' binding modalities producing a binding affinity in the range of -10.366 to -8.037. Theoretical results were in good accord with the observed experimental values. The docking score of compound 4e was -10.366, and the Glide energy was -66.459 kcal/mol.

Hybrid Bioactive Heterocycles as Potential Antimicrobial Agents: A Review.

The ever increasing cases of microbial resistance pose a major threat to the scientific community and therefore the need for discovery and development of newer antimicrobial agents with novel mode of action is becoming critical. One of the ways to tackle this herculean problem is to generate hybrid molecules by combining two or more bioactive heterocyclic moieties in a single molecular platform. The review here describes published results of our research group's endeavors towards development of potential new and safe antimicrobial agents with better effectiveness by using the hybrid approach. In the present review article the landscaping of heterocycles like 4-thiazolidinones, benzimidazole and quinoline are described. Compounds displaying two of more fold antimicrobial activity are included in the review.

Thiazolidinedione compounds: a patent review (2010 - present).

INTRODUCTION: The prevalence of metabolic syndrome, obesity and insulin resistance has become an epidemic. Thiazolidinediones (TZDs) affect glucose and lipid metabolism in insulin-sensitive tissues, which in turn reduces the lipid content in the liver by modulating several mediators. TZD as a hypoglycemic agent decrease blood sugar levels. Researchers have also made an attempt to design novel compounds having core structure of TZD with other heterocycles to explore them for anticancer and antimalarial properties. The present review provides an extended study of chemistry and inhibitory activity of established drug candidates containing TZDs, viz. their patenting scenario. AREAS COVERED: In this review, authors have covered TZD-based antidiabetic, anticancer and antimalarial drugs. MEDLINE and PubMed searches, and freedom of information available through FDA, USPTO, EPO and other patent database were used for the preparation of review. EXPERT OPINION: Diabetes management is very important as the number of diabetic patients increased and therefore the present research article will be very much useful for the development of new molecules.

Design, Synthesis, and Biological Evaluation of 1,4-dihydropyridine Derivatives as Potent Antitubercular Agents.

A series of novel 1,4-dihydropyridine-3,5-dicarbamoyl derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via multicomponent Hantzsch reaction. The newly synthesized compounds were characterized by IR, (1) H NMR, (13) C NMR, and mass spectroscopy. The synthesized compounds 3a-p were screened for antitubercular activity. Among all the screened compounds, compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis with minimum inhibitory concentration of 0.02 µg/mL and SI > 500, making it more potent than first-line antitubercular drug isoniazid. In addition, these compounds displayed relatively low cytotoxicity.