Exploration of Indazole-Derived Oxadiazoles and Thiadiazoles as Potential Antimycobacterial Agents: Synthesis and In Silico Docking Analysis

Abstract

Objective: As part of our ongoing research in organic and medicinal chemistry, we have been investigating the chemical and biological properties of compounds that incorporate different heterocycles, such as fused 1,3,4-oxadiazole and 1,3,4-thiadiazole systems. In this study, we synthesized novel oxadiazolyl-thiadiazole hybrids and evaluated their antibacterial activity against several pathogenic bacteria, as well as their antitubercular efficacy against the Mycobacterium tuberculosis H37Rv strain, using moxifloxacin and rifampicin as positive controls. Methods: We synthesized a series of novel indazole-based 1,2,3-triazoles using 1-methyl-1H-indazole-3-carbohydrazide and various isothiocyanates, followed by antibacterial activity assessment using the Agar well dilution method. The structural identity of the newly synthesized compounds was confirmed through a combination of spectroscopic techniques, including ¹H and ¹³C NMR, IR, and mass spectrometry. In silico molecular docking studies were performed to assess the binding affinity of the synthesized ligands to the M. tuberculosis DNA gyrase active site (PDB ID: 5BS8). Additionally, pharmacokinetic properties, including absorption, distribution, metabolism, excretion, and toxicity (ADMET), were predicted using SwissADME and ADMETlab2.0. Results and Discussion: The synthesized compounds exhibited moderate to excellent antibacterial and antitubercular activity. Among them, the p-tolyl-substituted thiadiazole derivative demonstrated potent antibacterial activity against Bacillus subtilis, with a zone of inhibition of 36 ± 0.1 mm. Meanwhile, the m-nitrophenyl-substituted oxadiazole showed superior antitubercular activity against the H37Rv strain, with a minimum inhibitory concentration (MIC) of 4.0 ± 0.3 μM. Molecular docking studies revealed that the m-nitrophenyl-indazole derivative interacts with key amino acid residues within the active site of M. tuberculosis DNA gyrase, including Met127 (A), Arg128 (A), Ala126 (A), Ala90 (A), Ala74 (A), Tyr93 (A), Lys72 (A), Ser73 (A), and Asp89 (A). Furthermore, bioavailability, drug-likeness, and gastrointestinal absorption parameters were evaluated in detail using the BOILED-Egg method based on SMILES notations. Conclusions: These findings suggest that oxadiazole-thiadiazole conjugates represent a promising class of antimicrobial agents with potential for further development.