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

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Özçelik B., Karakaya G., Aytemir M., Hamdoun S., Oflaz O.

Istanbul Journal of Pharmacy, cilt.54, sa.3, ss.446-455, 2024 (ESCI)

Özet

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