5-indole-appended 1,3,4-Oxadiazole/Oxadiazolinethione hybrids: Synthesis, crystal structure, antimicrobial and antibiofilm evaluation.

Abstract

A series of eleven new 5-indole-appended 1,3,4-Oxadiazole/Oxadiazolinethione derivatives 5(a-k) was synthesized via nucleophilic substitution of 5-(1H-indol-2-yl)-1,3,4-oxadiazoline-2(3H)-thione (3) with sugar and non-sugar halides 4(a-k). The structures of the synthesized compounds were established by FT-IR, NMR, and high-resolution mass spectrometry, while single-crystal X-ray diffraction analysis unequivocally confirmed the structures of compounds 5d and 5j. Hirshfeld surface analysis revealed that the crystal packing of these compounds is predominantly governed by intermolecular interactions. The synthesized compounds 5(a-j) were evaluated for their antimicrobial potential against gram-negative (Escherichia coli, Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus) bacteria, as well as against Mycobacterium smegmatis. Most derivatives showed only weak antibacterial and antimycobacterial activity; however, compound 5j exhibited promising activity against S. aureus with a minimum inhibitory concentration MIC of 62.5 μg/mL. Despite their modest antimicrobial potency, several derivatives demonstrated notable antibiofilm activity. The compound 5a emerged as the most effective inhibitor of M. smegmatis biofilm formation, reducing biofilm biomass to 29% at 100 μg/mL. Against S. aureus, compounds 5a and 5g were the most active, reducing biofilm biomass to approximately 34% at the same concentration. To rationalize the observed biological activities, molecular docking studies were performed against DNA Gyrase B, revealing favourable binding of compounds 5j, 5g, and 5i within the ATP-binding pocket, with docking scores ranging from -7.0 to -7.6 kcal/mol. Furthermore, density functional theory (DFT) calculations provided insight into the electronic properties of these compounds (via molecular electrostatic potential maps) and their stability and reactivity in drug-receptor binding.