Rational design, synthesis and evaluation of chromone-indole and chromone-pyrazole based conjugates: Identification of a lead for anti-inflammatory drug

•Rationally designed hybrid molecules were identified as selective COX-2 inhibitors.•Enzyme immunoassay results were supported by NMR and mass spectral studies and molecular modelling.•Compound 8 also showed excellent analgesic activity.•pXRD and SEM analysis also supported the drug like properties of compounds 8 and 9.

Conjugates of chromone-indole and chromone-pyrazole were screened for cyclooxygenase-2 (COX-2), cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitory activities. Compounds 8 and 9 were identified as preferred inhibitors of COX-2 over the other two enzymes. Their IC50 for COX-2 was 29 nM and 20 nM, respectively and selectivity indices (SI) for COX-2 over COX-1 was 46 and 337. NMR, mass spectral studies and molecular modelling also indicated preferential interactions of compounds 8 and 9 with COX-2. Tested on albino mice against capsaicin induced algesia, compound 8 exhibited analgesic potential comparable to diclofenac. In addition to the biological profile, the desirable physico-chemical properties of these compounds make them promising leads for anti-inflammatory drugs.

Graphical abstractChromone and indole based moderate COX-2 inhibitors were transformed into selective and highly potent COX-2 inhibitors. Figure optionsDownload full-size imageDownload as PowerPoint slide