Shawish I, Nafie MS, Barakat A, Aldalbahi A, Al-Rasheed HH, Ali M, Alshaer W, Al Zoubi M, Al Ayoubi S, De la Torre BG, Albericio F, and El-Faham A
A series of pyrazolyl- s -triazine compounds with an indole motif was designed, synthesized, and evaluated for anticancer activity targeting dual EGFR and CDK-2 inhibitors. The compounds were tested for cytotoxicity using the MTT assay. Compounds 3h , 3i , and 3j showed promising cytotoxic activity against two cancer cell lines, namely A549, MCF-7, and HDFs (non-cancerous human dermal fibroblasts). Compound 3j was the most active candidate against A549, with an IC 50 of 2.32 ± 0.21 μM. Compounds 3h and 3i were found to be the most active hybrids against MCF-7 and HDFs, with an IC 50 of 2.66 ± 0.26 μM and 3.78 ± 0.55 μM, respectively. Interestingly, 3i showed potent EGFR inhibition, with an IC 50 of 34.1 nM compared to Erlotinib (IC 50 = 67.3 nM). At 10 μM, this candidate caused 93.6% and 91.4% of EGFR and CDK-2 inhibition, respectively. Furthermore, 3i enhanced total lung cancer cell apoptosis 71.6-fold (43.7% compared to 0.61% for the control). Given the potent cytotoxicity exerted by 3i through apoptosis-mediated activity, this compound emerges as a promising target-oriented anticancer agent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with the authors AB, AA, HA-R, and MA at the time of review., (Copyright © 2022 Shawish, Nafie, Barakat, Aldalbahi, Al-Rasheed, Ali, Alshaer, Al Zoubi, Al Ayoubi, De la Torre, Albericio and El-Faham.)