Potential Antitubercular Agents Research Articles

Design, synthesis and characterization of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate as anti-tubercular agents: In silico screening for possible target identification.

A thorough search for the development of innovative drugs to treat tuberculosis, especially considering the urgent need to address developing drug resistance, we report here a synthetic series of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o) as potent anti-tubercular agents. These morpholino-indolizines were synthesized by reacting 4-morpholino pyridinium salts, with various electron-deficient acetylenes to afford the ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o). All synthesized intermediate and final compounds are characterized by spectroscopic methods such as 1H NMR, 13C NMR and HRMS and further examined for their anti-tubercular activity against the M. tuberculosis H37Rv strain (ATCC 27294-American type cell culture). All the compounds screened for anti-tubercular activity in the range of 6.25-50 μM against the H37Rv strain of Mycobacterium tuberculosis. Compound 5g showed prominent activity with MIC99 2.55 μg/mL whereas compounds 5d and 5j showed activity with MIC99 18.91 μg/mL and 25.07 μg/mL, respectively. In silico analysis of these compounds revealed drug-likeness. Additionally, the molecular target identification for Malate synthase (PDB 5CBB) is attained by computational approach. The compound 5g with a MIC99 value of 2.55 μg/mL against M. tuberculosis H37Rv emerged as the most promising anti-TB drug and in silico investigations suggest Malate synthase (5CBB) might be the compound's possible target.

Exploring rhodanine linked enamine-carbohydrazide derivatives as mycobacterial carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and molecular docking studies.

With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.

Pharmacophore, QSAR, molecular docking, molecular dynamics and ADMET study of trisubstituted benzimidazole derivatives as potent anti-tubercular agents

The objective of this study was to develop and verify a QSAR model for predicting the antitubercular effects of trisubstituted benzimidazole derivatives. For this study, 50 compounds with antitubercular activity targeting FtsZ protein were retrieved from published studies. The PharmaGist web server was used to create the pharmacophore model. The best pharmacophore model had seven special features and a score of 56.79. Molecular descriptors were computed using PaDEL-descriptor software and the ChemDes web server. A predictive QSAR model was created using the QSARINS software. The best QSAR Model 4, which had R2: 0.9114, R2adj: 0.8924, LOF: 0.1131, Q2-F1: 0.6499, Q2-F2: 0. 6499, Q2-F3:0.8356; and CCCext: 0.8522 identified a good fit. The descriptors AATS8e, AATSC7p, SpMin2_Bhm, nHBint6, SHssNH, and XLogP were essential for antitubercular activity. Molecular descriptors, such as SpMin2_Bhm, nHBint6, SHssNH, and XLogP positively contributed to the antitubercular activity. Molecular descriptors such as AATS8e and AATSC7p were negatively associated with antitubercular activity. From the above data, we have designed four series of trisubstituted benzimidazole derivatives, including 1A–E, 2A–E, 3A–E and 4A–E. All these newly designed compounds were used for molecular docking simulation and ADMET studies. Compound 1B exhibited the best ADMET features and highest binding affinity. Consequently, it was subjected to dynamic simulations for 100 ns. The binding stability of the FtsZ protein-compound 1B complex was confirmed by RMSD, RMSF, H-bond interaction, and percentage occupancy.

Development and evaluation of new oxindole derivatives as potential anti-tubercular agents

Tuberculosis (TB), which affects the lungs and other parts of the body, claims the lives of around 3 million people. Indolin-2-one derivatives were identified as a novel anti-tubercular series from Microplate Alamar Blue Assay (MABA) method, along with its synthesis, characterisation, molecular docking, and molecular dynamic simulations. The enzyme decaprenylphosphoryl-β-D-ribose 20-oxidase (DprE1) demonstrated high binding interaction energies associated with these compounds, which were investigated through the use of the docking technique. A conventional dynamic simulation study lasting 20 ns was used to assess the interaction's stability. The parameters derived from the trajectories of molecular dynamic simulation were computed and validated with respect to the stability of the protein-ligand complex under dynamic conditions. The absorption-distribution-metabolism-excretion (ADME) values are favourable for all of the synthesized compounds. After testing each novel compound for in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), the most promising lead analogues were 9e (MIC: 1.56 μg/mL), 13b (MIC: 3.125 μg/mL), and 13e (MIC: 3.125 μg/mL). In this study, we have designed and produced new 5-substituted Oxindole derivatives as anti-tubercular drugs through the application of docking and molecular dynamic modeling. Given the increasing demand for novel antibiotics and the ensuing urgent need for novel anti-TB medications, we think the currently reported oxindole derivatives of DprE1 inhibitors present an excellent possibility for future optimization.

Design of Cyclobut-3-Ene-1,2 Dione Derivatives as Anti-tubercular Agents

Introduction: Recent studies have shown modified cyclobutene derivatives as potent anti- tubercular agents, and the discovery of drugs against strains of Mycobacterium tuberculosis is still a crucial challenge in the modern world. Objective: The objective of the present study is to design and perform molecular docking studies and in-silico analysis of some novel cyclobut-3-ene-1,2 Dione derivatives with the aim of creating new, potential Mtb ATP synthase inhibitors. Materials and Methods: The structures of 24 compounds of diamino-substituted cyclobut-3-ene-1,2 Dione derivatives against Mtb ATP synthase were drawn using ChemSketch. Further, molecular docking and in-silico studies for the prediction of drug-likeness and pharmacokinetic parameters were carried out. Results: The docking studies of the novel compounds were done, and they had a better docking score with a good binding affinity towards the protein molecule. The synthesized compounds also comply with the in-silico prediction of drug-likeness and pharmacokinetic parameters and have shown good activity against Mtb ATP synthase. Conclusion: The current study shows that the cyclobut-3-ene-1,2 Dione derivatives can serve as a better lead molecule against Mtb ATP synthase and can be involved in further drug discovery

Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, Synthesis, In vitro biological evaluation, molecular docking and ADME studies

In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds’ selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC50 > 300 μg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability.

Synthesis and biological evaluation of novel hybrid compounds bearing pyrazine and 1,2,4-triazole analogues as potent antitubercular agents

In this study, we synthesized a series of hybrid compounds (T1–T18) containing pyrazine and 1,2,4-triazole moiety and assessed their effectiveness against mycobacterium tuberculosis.

Design, synthesis and in silico docking techniques of new 1,2,3-triazolylpyrrolidines bearing chalcone derivatives: Discovery of potent antitubercular agents

Compounds with a pyrrolidine scaffold play an important role in organic synthesis and especially in the synthesis of bioactive organic compounds, therefore, the development of new methods for modifying this scaffold is a very interesting framework of this study. We developed a rational approach for the synthesis of 1,2,3-trazolylchalcone substituted pyrrolidines derivatives, which were then examined using a variety of spectroscopic techniques such as 1H NMR, 13C NMR, FT-IR, mass spectroscopy and elemental analysis. Biological profiles showed that compounds 5e, 5h had better antibacterial inhibitory potency against S. aureus, E. coli with zone of inhibition 34 ± 0.1, 33 ± 0.3 mm, whereas 5a, 5e showed potent antifungal activity against C. parapsilosis, A. flavus with dimeter zone of inhibition 26 ± 0.2, and 30 ± 0.2 mm respectively. Among the tested compounds 5b, and 5h were the most potent antitubercular activity against Mycobacterium tuberculosis H37Rv and showing MIC values 5.23 µg/mL, 6.85 µg/mL respectively, which are similar activity that of the standard Streptomycin (MIC = 5.02 µg/mL). The binding mode for compound 5 inside the catalytic pocket of M. tuberculosis cytochrome P450 CYP121A1 and produced a network of hydrophobic and hydrophilic interactions (6GEO). From docking results, 5b demonstrated highly stable binding amino acids SerA:237, ArgA:386, ArgA:286, CysA:345, MetA:62, GlnA:385, AspA:282, PheA:280, LeuA:284, ValA:83, ProA:285, AlaA:337, HisA:343, AsnA:74, and ThrA:65, which are plays a crucial role in ensuring efficient binding of the ligand in a crystal structure of tubercular receptor. Furthermore, the physicochemical and ADME (absorption, distribution, metabolism, and excretion) filtration molecular properties, estimation of toxicity, and bioactivity scores of these scaffolds were evaluated.

In vitro and in silico exploration of newly synthesized triazolyl- isonicotinohydrazides as potent antitubercular agents

In the present study, we have reported the synthesis of novel isoniazid-triazole derivatives (4a-r), via the click chemistry approach. The synthesized isoniazid-triazole derivatives have potent in vitro antitubercular activity against the Mycobacterium tuberculosis (MTB) H37Rv strain. Among these compounds, 4b, 4f, 4g, 4j, 4k, 4m, 4o, 4p, and 4r were found to be the most active ones with a MIC value of 0.78 μg/mL. This activity is better than ciprofloxacin (MIC value = 1.56 μg/mL) and ethambutol (MIC value = 3.12 μg/mL). The compounds, 4a, 4c, 4d, 4e, 4h, 4i, 4l, and 4n have displayed activity equal to ciprofloxacin (MIC value = 1.56 μg/mL). The cytotoxicity of the active isoniazid-triazole derivatives was studied against RAW 264.7 cell line by MTT assay at 25 μg/mL concentration and no toxicity was observed. Moreover, in-vitro results were supported by in-silico studies with the known antitubercular target (PanK). The drug-likeness, density functional study, molecular docking, and molecular dynamics simulation studies of isoniazid-triazole derivatives validated the ability to form a stable complex with Pantothenate kinase (PanK), which will result in inhibiting the Pantothenate kinase (PanK). Therefore, the results obtained indicate that this class of compounds may offer candidates for future development, and positively provide drug alternatives for tuberculosis treatment.Communicated by Ramaswamy H. Sarma

Design, synthesis and molecular dynamic studies of novel imidazo/pyrido-pyrimidine clubbed ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate derivatives as potent anti-tubercular agents

A small library of substituted ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate was designed and synthesized. All the characterized molecules were screened for their anti-tubercular activity using the H37Rv strain of Mycobacterium tuberculosis (Mtb). The compounds 5c, 5d, 5f, 5h, and 5k showed equipotent activity (MIC 3.12 µg/mL), compounds 5b, 5e, 5g, 5i, and 5j were more potent (MIC 1.6 µg/mL), whereas, 5a and 5l shown moderate activity (MIC 6.25 µg/mL). The potent inhibitory activity of screened compounds was rationalized with in-silico molecular modeling studies against the Mtb-dihydrofolate reductase (DHFR) enzyme. Compound 5i displayed a good docking score of −8.56 Kcal/mole with H-bond and hydrophobic interactions. These interactions revealed the stability of the complex which in turn determined the potent inhibitory effect. To get in-depth mechanistic insight into the inhibitory effect and to assess the stability of the ligand–protein complex, a molecular dynamics (MD) simulation study was performed. The RMSD and RMSF values obtained by the MD simulation study were 2.39 Å and 0.92 Å, respectively. The obtained values suggested that the drug–ligand complex maintained the stability over entire 100 ns run and the molecule did not fluctuate. The H-bond and hydrophobic interactions displayed in molecular docking studies were found to be retained in the MD simulation run. The obtained MD simulation values indicate that the complex was stable and rationalize the potent inhibitory effect. The drug-likeliness properties of potent compounds were calculated and the values thus obtained suggested that the molecule 5i has drug-likeliness properties and complies with Lipinski's rule of five/Ro3. Hence, the identified compounds can be taken into further stages of drug discovery processes.

QSAR modeling, molecular docking, dynamic simulation and ADMET study of novel tetrahydronaphthalene derivatives as potent antitubercular agents

BackgroundTuberculosis is an air-borne contagious disease caused by slow-growing Mycobacterium tuberculosis (Mtb). According to Global Tuberculosis Report 2022, 1.6 million people were infected by tuberculosis in 2021. The continuing spread of drug-resistant tuberculosis (TB) is one of the most difficult challenges to control the tuberculosis. So new drug discovery is essential to the treatment of tuberculosis. This study aims to develop a QSAR model to predict the antitubercular activity of tetrahydronaphthalene derivatives. The QSARINS was used in this study to develop the QSAR predictive model.ResultsA number of tetrahydronaphthalene derivatives with MIC90 values were obtained from the literature to develop the QSAR predictive model. The compounds were divided into two sets: a training set consisting of 39 compounds and a test set containing 13 compounds. The best predictive Model 4 has R2: 0.8303, Q2LOO: 0.7642, LOF: 0.0550, Q2-F1: 0.7190, Q2-F2: 0.7067, Q2-F3: 0.7938 and CCCext: 0.8720. Based on the developed QSAR equation, the new compounds were designed and subjected to molecular docking, molecular dynamics and ADMET analysis.ConclusionIn the QSAR model, the molecular descriptors of MATS8s, Chi4, bcutv8, Petitjeant and fr_aniline were highly influenced the antitubercular activity. The developed QSAR model helps to predict the antitubercular activity of tetrahydronaphthalene derivatives.

Novel indolinone-tethered benzothiophenes as anti-tubercular agents against MDR/XDR M. tuberculosis: Design, synthesis, biological evaluation and in vivo pharmacokinetic study

Joining the global effort to eradicate tuberculosis, one of the deadliest infectious killers in the world, we disclose in this paper the design and synthesis of new indolinone-tethered benzothiophene hybrids 6a-i and 7a-i as potential anti-tubercular agents. The MICs were determined in vitro for the synthesized compounds against the sensitive M. tuberculosis strain ATCC 25177. Potent compounds 6b, 6d, 6f, 6h, 7a, 7b, 7d, 7f, 7h and 7i were furtherly assessed versus resistant MDR-TB and XDR-TB. Structure activity relationship investigation of the synthesized compounds was illustrated, accordingly. Superlative potency was unveiled for compound 6h (MIC = 0.48, 1.95 and 7.81 µg/mL for ATCC 25177 sensitive TB strain, resistant MDR-TB and XDR-TB, respectively). Moreover, validated in vivo pharmacokinetic study was performed for the most potent derivative 6h revealing superior pharmacokinetic profile over the reference drug. For further exploration of the anti-tubercular mechanism of action, molecular docking was carried out for the former compound in DprE1 active site as one of the important biological targets of TB. The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency.

Molecular Modeling of Enoyl Acyl Carrier Protein Reductase Inhibitors for Mycobacterium tuberculosis and their Pharmacokinetic Predictions

Tuberculosis (TB) is a deep public health concern worldwide worsened by reported multi drugresistant (MDR) and extensively drug- resistant (XDR) stralins of Mycobacterium tuberculosis, the causative agent of the disease. A new class of thiadiazole inhibitors were reported to inhibit the enoyl-acyl transporter protein reductase (InhA) of Mycobacterium tuberculosis (MTb). We performed here the computer-aided molecular design of novel thiadiazole (TDZ) inhibitors of InhA by in situ modifying the reference crystal structure of (S)-1-(5-((1-(2,6-difluorobenzyl)-1 H-pyrazol-3yl)amino)-1,3,4-thiadiazol-2-yl)-1-(4-methylthiazol-2-yl)ethanol-InhA (PDB code: 4BQP). Thus a training set of 15 hybrids with known inhibition potency \(\left(\mathrm{IC}_{50}^{\exp }\right)\) was selected to establish a onedescriptor quantitative structure-activity relationship (QSAR) model resulting in a linear correlation between the Gibbs free energy (GFE) during the formation of the InhA-TDZ complex and \(\mathrm{IC}_{50}^{\mathrm{exp}}\left(\mathrm{plC} \mathrm{C}_{50} \exp ==-0.29 \mathrm{x} \Delta \Delta \mathrm{G}_{\mathrm{com}}+8.13 ; \mathrm{n}=15 ; \mathrm{R}^2=0.92, \mathrm{R}^2{ }_{\mathrm{xv}}=0.91 ;\right.\) F-test of \(142.6 ; \sigma=0.21 ; \alpha>\) \(\left.95 \% ; R^2-R_{x v}^2=0.01\right)\). The 3D pharmacophore model \((\mathrm{PH} 4)\) generated from the active conformations of TDZs ( \(\mathrm{pIC}_{50}^{\mathrm{exp}}=0.93 \times \mathrm{pIC}_{50}^{\text {pred }}+0.47 ; \mathrm{n}=15 ; \mathrm{R}^2=0.97 ; \mathrm{R}_{\mathrm{xv}}=0.94 ;\) F-test of \(215.45 ; \sigma=0.17 ; \alpha>98 \% ; R^2-R_{x v}^2=0.03\) ) served as a virtual screening tool for new analogs from a virtual library (VL). The combination of molecular modeling and \(\mathrm{PH} 4\) in silico screening of (\(\mathrm{VL}\)) resulted in the identification of novel potent antitubercular agent candidates with favorable pharmacokinetic profiles of which the six best hits predicted inhibitory potencies \(\mathrm{IC}_{50}^{\text {pre }}\) in the sub nanomolar range \((0.1-0.2 \mathrm{nM})\).

Synthesis and Structure-Activity Relationships of a New Class of Oxadiazoles Targeting DprE1 as Antitubercular Agents.

The continuing prevalence of drug-resistant tuberculosis threatens global TB control programs, highlighting the need to discover new drug candidates to feed the drug development pipeline. In this study, we describe a high-throughput screening hit (4-benzylpiperidin-1-yl)(1-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methanone (P1) as a potent antitubercular agent. Structure-activity guided synthesis led to the discovery of several analogs with high in vitro potency. P1 was found to have promising potency against many drug-resistant strains, as well as drug-susceptible clinical isolates. It also showed cidality against Mtb growing in host macrophages. Whole genome sequencing of genomic DNA from resistant mutants raised to P1 revealed mutations in decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1). This novel oxadiazole scaffold expands the set of chemical tools for targeting a well-validated pathway to treat tuberculosis.

Identification of the Seaweed Metabolites as Potential Anti-tubercular Agents Against Human Pantothenate synthetase: An In Silico Approach.

Tuberculosis is the disease which is caused due to the contagion of Mycobacterium tuberculosis. The multidrug resistance Mycobacterium tuberculosis is the main hassle in the treatment of this worldwide health threats. Pantothenate synthase is a legitimate goal for rational drug designing against Mycobacterium tuberculosis. The enzyme is most active in the presence of magnesium or manganese. Marine algal cell wall is rich in sulfated polysaccharides such as fucoidans (brown algae), κ-carrageenans (red algae), and ulvan (green algae) with various favorable biological activities such as anticoagulant, antiviral, antioxidative, anticancer, and immunomodulating activities. In this study, we have modeled binding modes of selected known anti-tubercular compounds and different solvent extract against pantothenate synthase using advanced docking program AutoDock 4.2 tool. In our current study, in silico experiments were carried out to determine if fucoidan, κ-carrageenan, and ulvan sulfated polysaccharides could be a potential target against PANc (pantothenate synthetase), with the goal of identifying potential inhibitors as anti-TB leads targeting PANc for further wet lab validation. Two bioactive compounds were docked to the Mtb pantothenate synthetase protein binding site, with docking scores ranging from -5.57 to -2.73. κ-carrageenan had the best pose and docking score, with a Ligand fit score of -5.815. Ulvan did not dock with the protein. The molecular dynamics simulations were conducted with substrate and ligand bounded fucoidan and κ-carrageenan for 150ns and the protein Mtb pantothenate synthetase showed a stable conformation in the simulation, with tight amino acid contributions binding to the ligand molecule. RMSD characterizes the conformation and stability of protein ligand complexes, with higher fluctuations indicating low stability and minimal low-level fluctuations indicating equilibration and stability. The graph for RMSF shows significant peaks due to fluctuations in active site regions and other peaks indicating the adaptation of the ligand molecule to the protein binding pocket. From the molecular dynamics study, it is clear that the compounds are having good binding affinity in the active site. The root mean square deviation, root mean square fluctuations, and radius of gyration are supportive evidences which helped us to conclude that the compounds κ-carrageenan and fucoidan are suitable lead molecules for inhibiting pantothenate synthetase. Based on these evidences, the natural compounds from seaweeds can be tested clinically either alone or in combinations against the protein, which could facilitate the designing or the synthesis of new lead molecules as drugs against the tuberculosis.

Computational and photophysical probing interactions of newly synthesized benzothiazole azo-bonded molecules acting as potent antitubercular agents

In the present work, we have presented a very detailed study of unprecedented mono-azo benzothiazole derivatives. The targeted molecules were synthesized by a single-step involving diazotizing the primary aromatic amines followed by resultant diazonium salts coupling with N, N-Diethyl-m-toluidine (DEMT) through electrophilic substitution reaction influenced by positive mesomeric effect (+M effect) under suitable experimental conditions. The FT-IR, UV–vis, Photoluminescence (PL), 1H NMR, 13C NMR, and HRMS techniques were used to investigate the synthesized mono-azo benzothiazole dye derivatives. Additionally, for the first time, calculations based on density functional theory have been used to examine the ground state geometry, electronic structure, and molecular characteristics potential region maps of four benzothiazole mono-azo architectures (CR1-CR4). The effectiveness of the synthesized dye colourants against M. tuberculosis, H37Rv was assessed by utilizing the agar well diffusion assay method (ATCC 27,294), amongst the studied mono-azo derivatives, CR3 and CR4 exhibited a good zone of inhibition compared to CR1 and CR2. The compound CR1 demonstrated sensitivity at 20 µM, compared to 48.2 µM for the reference gentamicin. The antibacterial activity of the CR1 and CR4 compounds was revealed to have a 19 mm zone of inhibition. The derivative CR1 displayed 42.86 and CR3 displayed 38.75 of the concentration IC50 in 100 μl/ml, respectively, based on their cytotoxic potentiality.

Synthesis, biological evaluation and docking studies of silicon incorporated diarylpyrroles as MmpL3 inhibitors: An effective strategy towards development of potent anti-tubercular agents

Growing global demand for new molecules to treat tuberculosis has created an urgent need to develop novel strategies to combat the menace. BM212 related compounds were found to be potent anti-TB agents and they inhibit mycolic acid transporter, MmpL3, a known potent drug target from Mycobacterium tuberculosis. In order to enhance their inhibitory potency, several silicon analogues of diarylpyrroles related to BM212 were designed, synthesized, and evaluated for anti-tubercular activities. In Alamar blue assay, most of the silicon-incorporated compounds were found to be more potent than the parent compound (BM212), against Mycobacterium tuberculosis (MIC = 1.7 μM, H37Rv). Docking results from the crystal structure of MmpL3 and silicon analogues as pharmacophore model also strongly correlate with the biological assays and suggest that the incorporation of silicon in the inhibitor scaffold could enhance their potency by stabilizing the hydrophobic residues at the binding pocket. The best docking hit, compound 12 showed an MIC of 0.1 μM against H37Rv with an acceptable in vitro ADME profile and excellent selectivity index. Overall, the present study indicates that, the designed silicon analogues, especially compound 12 could be a good inhibitor for an intrinsically flexible drug-binding pocket of MmpL3 and has potential for further development as anti-tubercular agents.

2,6-Disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines as a new class of potent antitubercular agents inhibiting DprE1

Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC99 of 4 μM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 μM against Mtb H37Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 μL/min/mg), sufficient aqueous solubility (>90 μM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64, lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-β-d-ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb H37Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.

Synthesis of New Amide Linked Biphenoloxy 1,2,3-Triazoles as Antitubercular and Antimicrobial Agents

New 1,2,3-triazoles bearing biphenoloxymethyl and acetanilido moieties (5a-5l) have been synthesized, starting from 4-phenylphenol (1) following click chemistry approach. The synthesized compounds have been thoroughly characterized by their 1H NMR, 13C NMR and HRMS spectral data. These compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and antimicrobial activity against pathogenic microbia. Among the screened compounds, 5a and 5i have displayed notable antitubercular activity with MIC 25 µg/mL. Compounds 5a, 5b, 5c, 5 g, 5i and 5 l have shown effective inhibition against most of tested pathogens. Molecular docking results of compounds 5a and 5i show the binding modes of the synthesized compounds into the active site of mycobacterial enoyl reductase. The synthesized compounds have also been analyzed for their ADME properties. By considering all these results, the present research work will offer a promising lead series for discovery of emerging potent antitubercular agents.

Design, synthesis, computational molecular docking studies of novel heterocyclics bearing 1,2,4–triazole, 1,3,4–oxadiazole conjugates as potent antibacterial and antitubercular agents

Herein, we report the synthesis, and characterization of a new series of 1,3,4–oxadiazole and 1,2,4–triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1H NMR, 13C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b, 6d, and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 μg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 μg/mL respectively. Particularly, the prepared scaffolds 8c, 8d, and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 μg/mL against A. flavus and 6d, 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 μg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H37Rv with MICs 3.26, and 6.48 μg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H–bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME. Communicated by Ramaswamy H. Sarma