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, ¹H NMR, ¹³C 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.     

Design,synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐oxadiazole derivatives

A new antitubercular agents, benzo[6,7]cyclohepta[1,2‐b]pyridine‐1,3,4‐ oxadiazole hybrids ( 6a–o ), have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene, characterized by IR,¹H NMR,¹³C NMR, and HRMS, and further confirmed by X‐ray analysis. All the newly synthesized compounds 4a–o evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294). Among the compounds tested, the compounds 4o (MIC: 1.56  μg/ml) and 4l, 4m (MIC: 3.125  μg/ml) are promising lead analogues and have shown lower cytotoxicity.     

Design,synthesis, and evaluation of novel diphenyl ether derivatives against drug‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis

In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives ( 5a – f , 6a – f ) were designed and synthesized. The representative compounds showed promising in vitro activity against drug‐susceptible, isoniazid‐resistant, and multidrug‐resistant strains of Mycobacterium tuberculosis with MIC values of 1.56 μg/ml ( 6b ), 6.25 μg/ml ( 6a–d ), and 3.125 μg/ml ( 6b–c ), respectively. All the synthesized compounds exhibited satisfactory safety profile (CC₅₀ > 300 μg/ml) against Vero and HepG2 cells. Reverse phase HPLC method was used to probe the physicochemical properties of the synthesized compounds. This series of compounds demonstrated comparatively low logP values. pKa values of representative compounds indicated that they were weak acids. Additionally, in vitro human liver microsomal stability assay confirmed that the synthesized compounds possessed acceptable stability under study conditions. The present study thus establishes compound 6b as the most promising antitubercular agent with acceptable drug‐likeness.     

Novel Glycoconjugate of 8‐Fluoro Norfloxacin Derivatives as Gentamicin‐resistant Staphylococcus aureus Inhibitors: Synthesis and Molecular Modelling Studies

Antibiotic resistance has been the subject of interest in clinical practice due to high prevalence of antibiotic‐resistant pathogenic organisms. In view of the prevalence of lesser resistance in antibiotics belonging to aminoglycoside class of compounds viz. Food and Drug Administration‐approved gentamicin for the treatment of Staphylococcus infections, which also has instances of resistance in the clinical isolates of Staphylococcus aureus, a series of novel glycoconjugates of 8‐fluoro norfloxacin analogues with high regio‐selectivity by employing copper (I)‐catalyzed 1, 3‐dipolar cycloaddition of 1‐O‐propargyl monosaccharides has been synthesized and evaluated for the antibacterial activity against gentamicin resistance Staphylococcus aureus. Among these compounds, the compound 10g showed better antibacterial activity (MIC = 3.12  μ g/ml) than gentamicin (Escherichia coli (12.5  μ g/ml), Staphylococcus aureus (6.25  μ g/ml) and Klebsiella pneumonia (6.25  μ g/ml), including gentamicin resistant (>50  μ g/ml) strain in vitro). The docking studies suggest DNA gyrase of Staphylococcus aureus as a probable target for the antibacterial action of compound 10g .     

Synthesis and Antitubercular Screening of [(2‐Chloroquinolin‐3‐yl)methyl] Thiocarbamide Derivatives

A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, ¹H and ¹³C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g , 3h , 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity.     

4‐Substituted thieno[2,3‐d]pyrimidines as potent antibacterial agents: Rational design,microwave‐assisted synthesis,biological evaluation and molecular docking studies

In an attempt to discover a new class of antibacterial agents with improved efficacy and to overcome the drug‐resistant problems, some novel 4‐substituted thieno[2,3‐d]pyrimidines have been synthesized via microwave‐assisted methodology and evaluated for their in vitro antibacterial activity against various pathogenic bacterial strains. Compounds 12 b and 13 c showed the promising inhibitory potencies against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli with MICs ranging from 2 to 10 μg/ml. Compound 13 c was also found to be highly potent against methicillin‐resistant S. aureus (MRSA) with MIC value of 4 μg/ml. Docking simulation studies have been performed to unravel the mode of action and association study indicate the binding of potent compounds with DHPS enzyme. In silico ADME studies suggest the drug‐like characteristics of the potent compounds.     

Design,Synthesis, and in vitro antitubercular activity of 1,2,3‐triazolyl‐dihydroquinoline derivatives

In the quest for new active molecules against Mycobacterium tuberculosis, a series of dihydroquinoline derivatives possessing triazolo substituents were efficiently synthesized using click chemistry. The structure of 6l was evidenced by X‐ray crystallographic study. The newly synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The compounds 6a , 6g, and 6j (MIC: 3.13 μg/ml) showed promising activity when compared to the first‐line drug such as ethambutol. In addition, the structure and antitubercular activity relationship were further supported by in silico molecular docking studies of the active compounds against 3IVX.PDB (crystal structure of pantothenate synthetase in complex with 2‐(2‐(benzofuran‐2‐ylsulfonylcarbamoyl)‐5‐methoxy‐1H‐indol‐1‐yl)acetic acid).     

Design and synthesis of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs as bacterial peptide deformylase inhibitors

Herein, we report the synthesis and screening of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC₅₀ value = 139.28 μm ), 11g (IC₅₀ value = 136.18 μm ), and 11h (IC₅₀ value = 131.65 μm ) had shown good PDF inhibition activity. The compounds 11b (MIC range = 103.36–167.26 μg/mL), 11g (MIC range = 93.75–145.67 μg/mL), and 11h (MIC range = 63.61–126.63 μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range = 100.00–250.00 μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.     

Novel 3‐Substituted Ocotillol‐Type Triterpenoid Derivatives as Antibacterial Candidates

Plant‐derived triterpenoid saponins are involved in the plant defense system by targeting bacterial membranes. A series of ocotillol‐type triterpenoid derivatives were synthesized starting from PPD, one of the main components of Panax ginseng and their antibacterial activity against several representative bacteria were evaluated. Compounds 5 and 11 exhibited excellent antibacterial activity with MIC values of 1 μg/mL against Staphylococcus aureus and 8 μg/mL and 4 μg/mL against Bacillus subtilis, respectively. Furthermore, when compounds 5 and 11 were combined with two commercial antibiotics kanamycin and chloramphenicol, they showed strong synergistic activity at sub‐MIC levels against S. aureus USA300 and B. subtilis 168. Moreover, chloramphenicol turned from a bacteriostatic to a bactericidal agent when combined with compound 11 against B. subtilis 168.     

Synthesis,SAR Study and Evaluation of Mannich and Schiff Bases of Pyrazol-5(4H)-one Moiety Containing 3-(Hydrazinyl)-2-phenylquinazolin-4(3H)-one

In the present investigation, a series of 12 Mannich bases (QP1-12) and 5 Schiff bases (QSP1-5) of pyrazol-5(4H)-one moiety containing 3-(hydrazinyl)-2-phenylquinazolin-4(3H)-one has been synthesized and characterized by physicochemical as well as spectral means. The synthesized Mannich and Schiff bases were screened for their preliminary antimicrobial activity against Gram-positive and Gram-negative bacterial as well as fungal strains by the determination of zone of inhibition. Mannich bases (QP1-12) were found to be more potent antibacterial agents against Gram-positive bacteria, whereas Schiff bases (QSP1-5) were more potent against Gram-negative bacteria and fungi. Minimum inhibitory concentration result demonstrated that Mannich base compound (QP7) having ortho -OH and para -COOH group showed some improvement in antibacterial activity (minimum inhibitory concentration of 48.88×10⁻³ μM/ml) among the tested Gram-positive organisms and it also exhibit minimum inhibitory concentration of value of 12.22×10⁻³ μM/ml for Klebsiella pneumoniae. The antitubercular activity of synthesized compounds against Mycobacterium tuberculosis (H₃₇Rv) was determined using microplate alamar blue assay. Compound QP11 showed appreciable antitubercular activity (minimum inhibitory concentration of 6.49×10⁻³ μM/ml) which was more active than the standard drugs, ethambutol (minimum inhibitory concentration of 7.60×10⁻³ μM/ml) and ciprofloxacin (9.4×10⁻³ μM/ml). Compounds QP11, QP9, QSP1, QSP2, and QSP5 have good selective index and may be selected as a lead compound for the development of novel antitubercular agents.     

Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative

A series of novel hybrid molecules between sulfonamides and active antimicrobial 14‐o‐(3‐carboxy‐phenylsulfide)‐mutilin were synthesized, and their in vitro antibacterial activities were evaluated by the broth microdilution. Results indicated that these compounds displayed potent antimicrobial activities in vitro against various drug‐susceptible and drug‐resistant Gram‐positive bacteria such as Staphylococci and streptococci, including methicillin‐resistant Staphylococcus aureus, and mycoplasma. In particular, sulfapyridine analog ( 6c ) exhibited more potent inhibitory activity against Gram‐positive bacteria and mycoplasma, including Staphylococcus aureus (MIC = 0.016–0.063 μg/mL), methicillin‐resistant Staphylococcus aureus (MIC = 0.016 μg/mL), Streptococcus pneumoniae (MIC = 0.032–0.063 μg/mL), Mycoplasma gallisepticum (MIC = 0.004 μg/mL), with respect to other synthesized compounds and reference drugs sulfonamide (MIC = 8–128 μg/mL) and valnemulin (MIC = 0.004–0.5 μg/mL). Furthermore, comparison between MIC values of pleuromutilin‐sulfonamide hybrids 6a–f with pleuromutilin parent compound 3 revealed that these modifications at 14 position side chain of the pleuromutilin with benzene sulfonamide could greatly improve the antibacterial activity especially against Gram‐positives.     

Synthesis and Antimicrobial Activities of a Novel Series of Heterocyclic α‐Aminophosphonates

Two series of novel α‐aminophosphonates having heterocyclic moieties were synthesized in high yields. The structures of the newly synthesized compounds were confirmed by their elemental analyses, IR, ¹H NMR and MS spectral data. These compounds were screened for their antibacterial activities against Escherichia coli (NCIM2065) as a Gram‐negative bacterium, Bacillus subtilis (PC1219) and Staphylococcus aureus (ATCC25292) as Gram‐positive bacteria, and Candida albicans and Saccharomyces cerevisiae as fungi. The minimum inhibitory concentrations (MICs) of the synthesized compounds show high antibacterial and antifungal activities at low concentrations (10–1000 µg/mL). Furthermore, their lethal doses indicated that such compounds are safe for use as antimicrobial agents.     

Synthesis and biological evaluation of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione as antimycobacterial agents

Resistance among dormant mycobacteria leading to multidrug‐resistant and extremely drug‐resistant tuberculosis is one of the major threats. Hence, a series of 1,2,4‐triazole‐3‐thione and 1,3,4‐oxadiazole‐2‐thione derivatives ( 4a–5c ) have been synthesized and screened for their antitubercular activity against Mycobacterium tuberculosis H37Ra (H37Ra). The triazolethiones 4b and 4v showed high antitubercular activity (both MIC and IC₅₀) against the dormant H37Ra by in vitro and ex vivo. They were shown to have more specificity toward mycobacteria than other Gram‐negative and Gram‐positive pathogenic bacteria. The cytotoxicity was almost insignificant up to 100 μg/ml against THP‐1, A549, and PANC‐1 human cancer cell lines, and solubility was high in aqueous solution, indicating the potential of developing these compounds further as novel therapeutics against tuberculosis infection.     

Synthesis,biological evaluation,and molecular docking studies of novel 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles derivatives targeting Mycobacterium tuberculosis

A small library of new 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles was synthesized and screened for the antimycobacterial potency against Mycobacterium tuberculosis H₃₇Ra strain and Mycobacterium bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti‐TB activity in the range of IC₅₀0.03–5.88 μg/ml for dormant stage and 20 compounds in the range of 0.03–6.96 μg/ml for active stage. Their lower toxicity (>100 μg/ml) and higher selectivity (SI = >10) against all cancer cell lines screened make them interesting compounds with potential antimycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis for inhibition of M. tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4‐triazole analogues have an acceptable safety index, in vivo stability and bio‐availability.     

Comparative study of conventional and microwave-assisted synthesis of some Schiff bases and their potential as antimicrobial agents

A series of Schiff bases (compounds 1–10) were synthesized by condensing heterocyclic/aromatic aldehydes with heterocyclic/aromatic amines through both, conventional method and microwave-assisted synthesis. The compounds were confirmed by means of IR spectroscopy, Mass spectrometry, ¹H NMR and elemental analyses. The compounds were assayed for antibacterial activity against selected strains of Gram positive, Gram negative bacteria and some fungi by zone inhibition method. Minimum inhibitory concentration (MIC) was also determined for each compound. Reaction times were drastically reduced by microwave-assisted synthesis. MIC was as low as 50 μg/ml exhibited by compounds 2 (against Escherichia coli, Aspergillus niger and Penicillium chrysogenum) and 10 (against Bacillus subtilis). The study presents a series of potential antimicrobial agents through efficient and simple reactions and mild reaction conditions, thereby offering a green chemistry approach.     

Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐d]pyrimidin‐4(3H)‐one derivatives

5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐d]pyrimidin‐4(3H)‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum, E. coli, and S. aureus, indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.     

Design,synthesis, and structure–activity relationship studies of novel pleuromutilin derivatives having a piperazine ring

A series of novel pleuromutilin derivatives possessing piperazine moieties were synthesized under mild conditions. The in vitro antibacterial activities of these derivatives against Staphylococcus aureus and Escherichia coli were tested by the agar dilution method. Structure–activity relationship studies resulted in compounds 11b , 13b , and 14a with the most potent in vitro antibacterial activity among the series (minimal inhibitory concentration = 0.0625–0.125 μg/mL). The binding of compounds 11b , 13b , and 14a to the E. coli ribosome was investigated by molecular modeling, and it was found that there is a reasonable correlation between the binding free energy and the antibacterial activity.     

Synthesis of new bis‐pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti‐biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans

Literature reports suggest that pyrazoles and hydrazides are potential antimicrobial pharmocophores. Considering this fact, a series of nineteen conjugates containing hybrids of bis‐pyrazole scaffolds joined through a hydrazide linker were synthesized and further evaluated for their antimicrobial activity against a panel of Gram‐positive and Gram‐negative bacteria along with Candida albicansMTCC 3017 strain. Although the derivatives exhibited good antibacterial activity, some of the derivatives ( 13d , 13j , 13l , 13p , and 13r ) showed excellent anti‐Candida activity with MICs values of 3.9 μg/ml, which was equipotent to that of the standard Miconazole (3.9 μg/ml), which has inspired us to further explore their anti‐Candida activity. The same compounds were also tested for anti‐biofilm studies against various Candida strains and among them, compounds 13l and 13r efficiently inhibited the formation of fungal biofilms. Field emission scanning electron micrographs revealed that one of the promising compound 13r showed cell damage and in turn cell death of the Candida strain. These potential conjugates ( 13l and 13r ) also demonstrated promising ergosterol biosynthesis inhibition against some of the strains C. albicans, which were further validated through molecular docking studies. In silico computational studies were carried out to predict the binding modes and pharmacokinetic parameters of these conjugates.     

Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5‐Benzodiazepine Derivatives as Potential Antimicrobial Agents

A series of novel 1,5‐benzodiazepine derivatives were rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of 1,5‐benzodiazepine, pyridine (phenyl), and an ester group. The structures of the target compounds were determined by ¹H NMR, ¹³C NMR, MS, IR, and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi C. neoformans, C. neoformans clinical isolates (ATCC 32264), C. albicans (ATCC 10231), Gram‐negative bacterium E. coli (ATCC 44752), and Gram‐positive bacterium S. aureus (ATCC 25923). The results of the bioactive assay demonstrated that most of the tested compounds exhibited variable inhibitory effects on the growth of the tested microorganisms. All the active compounds showed better antifungal activity than antibacterial activity. Notably, compound 2b displayed the highest activity (MIC = 30 μg/mL) against C. neoformans and (MIC = 31 μg/mL) against C. neoformans clinical isolates. In addition, compound 2a also showed excellent activity against C. neoformans and C. neoformans clinical isolates with minimum inhibitory concentration of 35 and 36 μg/mL, respectively. Compounds 2a and 2b were further studied by evaluating their cytotoxicities, and the results showed that they have relatively low level cytotoxicity for BV2 and 293T cell. Preliminary structure‐activity relationship study on three diverse sets (C‐2, C‐3, and C‐8 positions) of 1,5‐benzodiazepines was performed. The results revealed that the presence of a ‐CH₃ group at the C‐8 position had a positive effect on the inhibitory activity of these compounds. Additionally, the 2‐pyridyl group at the C‐2 position may be a pharmacophore and ‐COOC₂H₅ at C‐3 position is the best substituent for the maintenance of antimicrobial activities.     

Discovery of the Highly Potent Fluoroquinolone‐Based Benzothiazolyl‐4‐thiazolidinone Hybrids as Antibacterials

A new series of fluoroquinolone‐based benzothiazolyl‐4‐thiazolidinone hybrids has been yielded via sulfated tungstate‐promoted highly accelerated N‐formylation at a piperazine residue of ciprofloxacin and norfloxacin entities. The formylated fluoroquinolone moieties were then coupled with substituted 2‐aminobenzothiazoles, which were generated from their respective para‐substituted amines to form corresponding Schiff base intermediates. The Schiff bases were then treated with thioglycolic acid to equip a new class of 4‐thiazolidinones to be analyzed for their antibacterial effects against two Gram‐positive (Staphylococcus aureus and Bacillus subtilis) and two Gram‐negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and were found highly potent with lowest Minimum inhibitory concentrations (MIC), 1–2 μg/mL, that is, more potent than control drugs ciprofloxacin (3.12–6.25 μg/mL). Initial outcomes provided for these novel molecular systems will aid researchers to design and develop new antibacterial drugs. The structural assignments of the new products were done on the basis of FT‐IR, ¹H NMR and ¹³C NMR spectroscopy, and elemental analysis.