Synthesis and antibacterial evaluation of 5-(3-nitrophenyl)-N′-arylisoxazole-3-carbohydrazide derivatives against carbapenem-resistant Acinetobacter baumannii

Abstract

The gram-negative coccobacillus Acinetobacter baumannii, a WHO critical priority pathogen and member of ESKAPE pathogen panel, threatens global health due to its substantial association with hospital-acquired infections as well as resistance exhibited to last-resort antibiotics, such as colistin, tigecycline and carbapenems. Thus, urgent drug discovery and development is essential, targeting Acinetobacter baumannii, especially carbapenem-resistant Acinetobacter baumannii (CRAB). In this context, we report the design, synthesis and anti-bacterial evaluation of a new collection of 5-(phenyl)-N′-arylisoxazole-3-carbohydrazides for their effectiveness against various bacterial pathogen panels. Amongst the various compounds synthesised, 7j, 7l, 7n, 7o, 7p, and 16 exhibited significant antibacterial activity against CRAB, with minimum inhibitory concentrations (MIC) 0.5–2 μg/mL. Compound 7l demonstrated the highest antibacterial effectiveness, with a 0.5 μg/mL MIC. Additional testing revealed that these compounds were non-toxic to Vero cells and displayed high selectivity indices. Furthermore, they were effective against clinical isolates of multidrug-resistant Acinetobacter baumannii (MDR-AB), with compound 7l showing bactericidal effects when paired with Rifampicin, as supported by time-kill kinetic studies. 3D QSAR confirms 7ls increased activity comes from good steric fit, ideal electrostatics, strategic hydrophobic placement, and precise H-bond acceptor/donor positioning, and 7l complies with Lipinski's rule of five. The molecular target for these compounds is not known, though in silico α-fold modelling indicate that KatG may be the probable target. However in-depth mechanistic studies need to be done to validate these in silico predictions, based on which 7l may be further optimised as a promising candidate targeting CRAB.