Design and synthesis of new series of chiral pyrimidine and purine analogs as COX-2 inhibitors: Anticancer screening, molecular modeling, and in silico studies

Two series of chiral novel compounds were designed and synthesized using a one-pot double Mannich-type reaction, with pyrimidine, purine, and purine bioisosteres as a central heterocyclic scaffold with a methylamino chain as a linear core 3a-e (formula A) or a purine nucleus as a central core bearing two vicinal phenyl and different heteroaryl moieties 5a-e (formula B). The NCI selected all the designed com-pounds for anticancer testing against 60 distinct human cancer cell lines. Compounds 3d and 5d demon-strated strong antitumor activity against a wide range of cancers, with mean growth inhibition of 59.61% and 44.30%, respectively. Both compounds showed the highest anticancer activity against breast cancer cell lines MCF-7 (94.62%, 99.76%) and MDA-MB-468 (85.81%, 92.64%). Interestingly, almost all leukemia cell lines were sensitive to both 3d and 5d Besides, compound 3d was sensitive to all-colon, ovarian, and prostate cancer cell lines. Additionally, the IC50 values of compounds 3d and 5d against the most sensi-tive leukemia (HL-60 (TB)), ovarian cancer (SK-OV-3), and breast carcinoma (MCF-7) cell lines were deter-mined to be ( 3d , IC50 = 11.96 +/- 2.74, 9.46 +/- 2.27, and 6.68 +/- 2.14 mu M) and ( 5d , IC50 = 17.89 +/- 2.19, 8.89 +/- 2.50, and 8.75 +/- 1.99 mu M), respectively. Both compounds exhibited strong antiproliferative activity that was nearly comparable to or half that of doxorubicin (IC50 = 12.54 +/- 2.10, 7.7 +/- 0.48, and 3.34 +/- 0.21 mu M) and about 2-and 3-fold better than 5-FU (IC50 = 19.99 +/- 2.81, 21.8 +/- 2.09, and 16.79 +/- 2.18 mu M). A COX-2 in-hibition assay was performed to assess the target compounds' ability to inhibit COX-2. Compounds 3d and 5d displayed interesting COX-2 inhibition activity, exerting IC50 values in the nanomolar range in comparison to celecoxib (IC50 = 53.76 +/- 2.05 nM). However, compound 3d exerted higher anti-COX-2 ac-tivity, with an IC50 value of 69.79 +/- 2.14 nM, than compound 5d (89.92 +/- 2.17 nM). Further, compound 3d was able to arrest cell growth at the S and G2/M phases, indicating apoptosis induction. Moreover, the molecular docking of both compounds revealed a high affinity for the COX-2 receptor, with energy scores (S) = -6.63 and -7.00 kcal/mol, which were comparable to celecoxib (S) = -6.42 kcal/mol. Besides, in silico studies of compounds 3d and 5d revealed good pharmacokinetics profiles, physicochemical features, and drug-likeness data that were nearly identical to celecoxib.(c) 2023 Elsevier B.V. All rights reserved.