Design, synthesis and biological evaluation of bivalent benzoxazolone and benzothiazolone ligands as potential anti-inflammatory/analgesic agents.

Abstract Benzoxazolone and benzothiazolone were used as template blocks to develop two series of dimers as anti-inflammatory and analgesic agents based on the concept of bivalent ligands. The first series ( I ) involved varying the carbon chain lengths extending from the piperazine core to the nitrogen atom of the dibenzo[ d ]oxazol-2(3 H )-one or dibenzo[ d ]thiazol-2(3 H )-one. The second series ( II ) was designed by changing the attachment point. All compounds were screened for their in vitro anti-inflammatory activity in terms of the inhibition of inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB). Seventeen compounds inhibited both targets. Eleven of them exhibited IC 50 values below 3 μM while five compounds showed IC 50 values of 1 μM or below. Most of the compounds were found to be devoid of cytotoxicity against mammalian kidney and solid tumors cell lines up to 25 μg/mL. In vivo anti-inflammatory and antinociceptive studies revealed that compounds 3j , 5t and 8b have significant anti-inflammatory and analgesic activity comparable to that of indomethacin and ketorolac, respectively.