Introduction: Mycobacterium tuberculosis has been a grievous pathogen causing staggering infections worldwide; especially its recently drug resistant strains are intractable. The MurA ligase of cell-wall peptidoglycan pathway is the suitable target often used for drug development. Methods: A homology model of MurA enzyme of M. tuberculosis was generated and validated by a Ramachandran plot for use in molecular docking studies with 13 cyano-compounds, along with 4 first-line anti-tuberculosis drugs, isoniazid, pyrazinamide, ethambutol and rifampicin. Results: Docking scores of two most effective cyano-compounds, pitipeptolides F and pitipeptolides D are -13.765 and -13.678 kcal/mol, respectively, whereas that of rifampicin is -9.173 kcal/mol. Computed LD50 values of the majority cyano-compounds were 200 mg/kg in mouse models, whereas that of isoniazid is 133 mg/kg. Most cyano-compounds, isoniazid and rifampicin are of the class III toxicity level or slightly toxic. Isoniazid has the highest LC50 value around 0.7 mmol against fathead minnow fish, but it is carcinogenic and mutagenic, as known from the computational prediction. Conclusion: Effective-most cyano-compounds, pitipeptolides F and pitipeptolides D could be used as alterative/ complementary agents against recently reported drug-resistant strains of M. tuberculosis.
Key words: Tuberculosis, MurA enzyme, Cyano-compounds, Antimycobacterial inhibitors, Computational toxicity study, Molecular docking.
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