Synthesis of Triazolylazetidinones as Promising Antitubercular Agents: Computational and Experimental Validation Targeting Polyphosphate Kinase 2
TL;DR
A series of novel 1,2,4-triazole-azetidin-2-one hybrids were designed and synthesised as potential anti-tubercular agents against polyphosphate kinase 2 (PPK2), an enzyme involved in nucleotide regulation in Mycobacterium tuberculosis.
Abstract
A series of novel 1,2,4-triazole-azetidin-2-one hybrids (A1-A12) were designed and synthesised as potential anti-tubercular agents. The compounds were synthesised via Schiff base formation followed by cyclocondensation reactions. The compounds were studied as anti-tubercular agents against polyphosphate kinase 2 (PPK2), an enzyme involved in nucleotide regulation in Mycobacterium tuberculosis. A three-dimensional model of PPK2 was generated and examined by molecular dynamics studies. Docking studies indicated favourable interactions of some compounds with amino acid residues ASN131, GLU136, LYS75 and ARG127 in the active site of PPK2, supporting their possible role as PPK2 inhibitors. ADMET simulation analysis revealed favourable physico-chemical and pharmacokinetic parameters, satisfying the criteria for oral drug-likeness. The anti-tubercular activity of compounds A1-A12 was evaluated against M. tuberculosis H37Rv using the minimum inhibitory concentration (MIC) method. Compounds A11 and A12 exhibited the highest activity with MIC values below 7.81 μg/mL, while the remaining derivatives showed moderate to weak activity. Cytotoxicity studies on Vero cells demonstrated concentration-dependent effects, and IC50 values indicated acceptable selectivity for compounds A1 and A12. Acute oral toxicity studies in mice established an LD50 value of 300 mg/kg. Histopathological examination of major organs revealed no significant structural changes at tolerated doses.