Marine‐Derived Aminopyrimidone and Aminoimidazole Alkaloids as Promising Inhibitors of Mycobacterium tuberculosis : An Integrated In Silico Approach

ABSTRACT The pharmacological potential of marine alkaloids is enormous due to their diverse bioactivities. In this work, we performed a comprehensive computational analysis of marine alkaloids, including Calcardine C, Ernstine A, Naamine H, Naamine I, Naamidine J, Naamidine K, Phorbatopsin D, and Phorbatopsin E, in connection with Mycothiol S‐conjugate amidase (MycoSCoA), an essential enzyme for Mycobacterium tuberculosis metabolism. Frontier molecular orbital (FMO) analysis and geometry optimization show that Naamidine J is the most stable compound; its low HOMO–LUMO gaps suggest high reactivity. According to electrostatic potential mapping, Naamidine K has the highest charge distribution, which is in line with a higher binding potential. The strong intramolecular charge transfer of the lead compounds was further confirmed by Natural Bond Orbital (NBO) analysis. Molecular docking studies show that Naamidine K and Naamidine J have the highest binding affinities with MycoSCoA (−10.6 and −9.3 kcal/mol, respectively). These substances use a range of hydrophobic and hydrogen bonding interactions to create stable complexes. It is noteworthy that Naamidine J exhibited superior binding to 4EWL (−9.3 kcal/mol), which was sustained by a network of hydrogen bonds and π‐interactions. The selectivity of the marine alkaloids was highlighted by the weakest interactions, which were shown by BOG and GOL. This in silico study highlights Naamidine K and J as promising candidates for further anti‐tuberculosis drug development in general.