Pyrrolyl thiadiazoles as Mycobacterium tuberculosis inhibitors and their in silico analyses

Shrinivas D Joshi,¹ Uttam A More,^1,2 Shailesh Sorathiya,¹ Deepshikha Koli,¹ Tejraj M Aminabhavi<sup>1

1</sup>Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, Soniya Education Trust’s College of Pharmacy, Dharwad, India; ²Centre for Research and Development, Prist University, Thanjavur, Tamil Nadu, India

Abstract: A novel series of pyrrolyl thiadiazoles was synthesized and tested for antimycobacterial activity against the Mycobacterium tuberculosis H₃₇Rv strain, using the microplate Alamar blue assay method. Molecular docking and in vitro minimum inhibitory concentration assays revealed that these molecules can be primarily screened for ENR inhibition, using the score values and H-bond interactions with amino acid residues Tyr158, Met98, and cofactor NAD⁺, which are the key interactions. For most of the molecules, hydrophobic interaction is the key factor affecting their antitubercular activity. The activity of -OCH₃, -NO₂, -F, pyridine, and sulfonamide substituted derivatives was better than that of -CH₃, -NH₂, -Cl, and -Br substituted derivatives, as per experimental and docking studies. Molecular modeling studies are in agreement with their biological evaluations.

Keywords: pyrroles, antitubercular activity, Surflex-Docking, enoyl-ACP reductase