Pioneering 1,3,5-triaryl pyrazolines as promising dual inhibitors of COX-2 and 15-LOX endowed with potent anticancer activity: design, synthesis, and in silico study

Despite selective COX-2 inhibitors existing, they do not fully meet the demand for safer anti-inflammatory drugs. COX-2 and 15-LOX dual inhibition offers a promising avenue for developing safer NSAIDs and may play a crucial role in the fight against Cancer. Thus, we designed and synthesized new 1,3,5-triaryl pyrazolines as dual COX-2/15-LOX inhibitors with potent Anticancer activity. The synthesized compounds were evaluated in vitro as dual COXs/15-LOX inhibitors and for Anticancer activity against human colorectal Cancer cell lines HT-29 and HCT116. The pyrazolines 4a, 4c, 5h, and 5i exhibited outstanding inhibition of the COX-2 isoenzyme (IC₅₀ = 0.013 - 0.022 μM), demonstrating potency equal to or surpassing celecoxib (IC₅₀ = 0.019 μM). Notably, compounds 4a and 4c exhibited COX-2 selectivity indices (SI = 1256.74 and 804.78, respectively), far surpassing celecoxib (SI = 178.79). Additionally, they showed potent 15-LOX inhibitory activities (IC₅₀ = 1.19 and 2.80 μM, respectively), outperforming NDGA (IC₅₀ = 5.29 μM). Also, the in vivo results indicated that compounds 4a and 4c exhibit non-ulcerogenic performance. Thus, they emerged as the most promising candidates for dual-selective inhibition of COX-2 and 15-LOX. Compound 5i demonstrated superior COX-2 inhibitory potency (IC₅₀ = 0.018 μM) along with substantial Anticancer activity against the HT-29 and HCT116 cell lines (IC₅₀ = 11.46 and 18.09 μM, respectively). This indicates that 5i could be a promising lead for the design of a potent anti-inflammatory candidate and provide a safer approach to Cancer prevention, particularly for colon Cancer. Molecular modeling has simulated potential binding interactions of our synthesized pyrazolines within the active sites of COX-2 and 15-LOX, and the MD simulations throughout 100 ns demonstrated stable binding complexes.

1,3,5-Triaryl pyrazoline; Anti-inflammatory; Anticancer; Dual COX-2/15-LOX.