Allomaltol derivatives as Antimycobacterial agents: In vitro and in silico evaluations with potential protein targets

Abstract

Background and Aims: Mycobacterium species cause life-threatening pulmonary and extrapulmonary diseases in humans. This study aimed to evaluate the potential antimycobacterial activity of allomaltol derivatives in the Mannich base structure in vitro and in silico. Methods: The antimycobacterial activity of each compound against Mycobacterium tuberculosis and Mycobacterium avium was tested using a resazurin microplate assay, and cytotoxicity was assessed using human MRC-5 and He-La cells. Using the SwissTarget tool, Rip1 protease, the metallo-beta-lactamase (MBL) superfamily protein, the serine protease Rv3671c, and zinc metalloprotease 1 (ZMP1) were identified as potential targets. Blind docking was performed for compound 14 using CB-Dock to identify and assess the most probable binding sites on the target proteins. Defined docking was performed with Flare to determine the best binding pose at the predicted binding pocket. The druglikeness of hit compounds, including the partition coefficient, number of hydrogen bond donors/acceptors, molecular refractivity, topological polar surface area (PSA), and gastrointestinal and blood-brain barrier absorption, were evaluated using the SwissADME tool. Results: Compounds with methyl-substituted piperidine groups were found to have antimycobacterial activity (MICs: 2 μg/mL) against M. avium, which was as potent as the clinically used drugs ethambutol and streptomycin. The predicted physicochemical properties of the four hit compounds were satisfactory. According to the docking results, the binding energies of compound 14, which showed the best overall antimycobacterial activity, ranged from -8.14 to -5.97 kcal/mol, with ZMP1 showing the lowest binding energy. Conclusion: The results of this study provide evidence that allomaltol derivatives are promising antimycobacterial agents with satisfactory drug profiles.

Keywords

• Allomaltol
• Tuberculosis
• Molecular Docking
• Druglikeness

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