Febuxostat-based amides and some derived heterocycles targeting xanthine oxidase and COX inhibition. Synthesis, in vitro and in vivo biological evaluation, molecular modeling and in silico ADMET studies

Various febuxostat derivatives comprising carboxamide functionalities and different substituted heterocycles were synthesized and evaluated for their biological activities as xanthine oxidase (XO) and cyclooxygenase (COX) inhibitors. All the tested compounds exhibited variable in vitro XO inhibitory activities (IC50 values 0.009-0.077 mu M), among which the analog 17 has emerged as the most potent derivative (IC50 0.009 mu M), representing nearly 3-times the potency of febuxostat (IC50 0.026 mu M). The same analogs were further investigated for their in vitro COX-1 and COX-2 inhibitory activity, where fifteen analogs demonstrated recognizable COX-2 inhibitory potential (IC50 values range 0.04 - 0.1 mu M), when correlated with celecoxib (IC50 0.05 mu M), together with appreciable selectivity indices. Compounds 5a, 14b, 17, 19c, 19e and 21b that showed significant in vitro XO and/or COX inhibitory potentials were further investigated for their in vivo hypouricemic as well as anti-inflammatory activities. Interestingly, the in vivo results were concordant with the collected in vitro data. Docking of compounds 5a, 14b, 17, 19c, 19e and 21b with the active sites of XO and COX-2 isozymes demonstrated superior binding profile compared with the reported ligands (febuxostat and celecoxib, respectively). Their docking scores were reasonable and cohering to a great extent with their corresponding in vitro IC50 values. Moreover, in silico computation of the predicted pharmacokinetic and toxicity properties (ADMET), together with the ligand efficiency (LE) of the same six compounds suggesting their liability to act as new orally active drug candidates with a predicted high safety profile.

Automated summary

Various febuxostat derivatives were synthesized and evaluated for their inhibitory activities on XO and COX enzymes. Some of these compounds showed potential in vitro anti-inflammatory and hypouricemic activities, with superior binding profiles to the active sites compared to existing drugs.