Activity Profiling of Nitro-Substituted Di(Hetero)Aryl 1,3,4- and 1,2,4-Oxadiazoles: Antimicrobial, Cholinesterase Inhibition and Antioxidant Potential

Oxadiazole derivatives represent a promising scaffold for drug discovery, offering therapeutic potential, notably against neurodegenerative diseases and microbial infections. Based on molecular hybridisation approach utilising bioactive oxadiazoles, pyridine-, quinoline- and nitrophenyl-based compounds, we designed novel 1,3,4- and 1,2,4-oxadiazole derivatives containing nitro group(s), evaluated their enzyme inhibition, antimicrobial, and antioxidant properties, and analysed their structure-activity relationships (SAR). Comprehensive activity assessments of them and their synthetic precursors revealed robust inhibitory activity against acetylcholinesterase with IC 50 values as low as 1.47 µM and butyrylcholinesterase (IC 50 ≥ 45.09 μM), outperforming rivastigmine in several cases. Mechanistic insights via molecular docking unveiled unique binding modes for cholinesterases inhibition. Antimicrobial screening demonstrated potent activity (MIC ≥ 2 μM) of several compounds against Mycobacterium tuberculosis, atypical mycobacteria, Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, and mould Trichophyton interdigitale. The antioxidant evaluation identified derivatives' free-radical scavenging potential. SAR analysis identified essential structural features, favouring 3,5-dinitrophenyl moiety and 1,3,4-oxadiazoles over 1,2,4-isomers and 1,2-diacylhydrazine precursors. In summary, novel candidates for addressing challenges in treating infectious diseases and disorders related to insufficient acetylcholine transmission were identified.