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Papers of the Week


Papers: 19 Oct 2024 - 25 Oct 2024


2024 Oct 17


RSC Med Chem


39430948

Design, synthesis, and evaluation of benzhydrylpiperazine-based novel dual COX-2/5-LOX inhibitors with anti-inflammatory and anti-cancer activity.

Authors

Saraf P, Bhardwaj B, Verma A, Siddiqui MA, Verma H, Kumar P, Srivastava S, Krishnamurthy S, Srikrishna S, Shrivastava SK

Abstract

Piperazine derivatives were screened using the ChEMBL database, paving the way for the design, synthesis, and evaluation of a novel series of dual COX-2/5-LOX inhibitors and identifying their role in mitigating cancer cell proliferation. Compound 9d with 4-Cl substitution at the terminal phenyl ring showed promising inhibition of COX-2 (IC = 0.25 ± 0.03 μM) and 5-LOX (IC = 7.87 ± 0.33 μM), outperforming the standards celecoxib (IC = 0.36 ± 0.023 μM) and zileuton (IC = 14.29 ± 0.173 μM), respectively. The two most active derivatives 9d and 9g indicated a significant anti-inflammatory response in a paw edema model by inhibiting PGE2, IL-6, and TNF-α and an increase in IL-10 concentrations. Interestingly, 9d effectively reduced pain by 55.78%, closely comparable to the 59.09% exhibited by the standard indomethacin, and was also devoid of GI, liver, kidney, and cardiac toxicity. Furthermore, 9d demonstrated anti-cancer potential against A549, COLO-205, and MIA-PA-CA-2 human cancer cell lines and an cancer model. The pharmacokinetic investigations revealed that 9d has good oral absorption characteristics.