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 IC50 values as low as 1.47 µM and butyrylcholinesterase (IC50 ≥ 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.