Pyrazolyl-s-triazine with indole motif as a novel of epidermal growth factor receptor/cyclin-dependent kinase 2 dual inhibitors

Ihab Shawish; Mohamed S Nafie; Assem Barakat; Ali Aldalbahi; Hessa H Al-Rasheed; M Ali; Walhan Alshaer; Mazhar Al Zoubi; Samha Al Ayoubi; Beatriz G De la Torre; Fernando Albericio; Ayman El-Faham

doi:10.3389/fchem.2022.1078163

Pyrazolyl-s-triazine with indole motif as a novel of epidermal growth factor receptor/cyclin-dependent kinase 2 dual inhibitors

Front Chem. 2022 Nov 25:10:1078163. doi: 10.3389/fchem.2022.1078163. eCollection 2022.

Authors

Ihab Shawish^{1

2}, Mohamed S Nafie³, Assem Barakat², Ali Aldalbahi², Hessa H Al-Rasheed², M Ali², Walhan Alshaer⁴, Mazhar Al Zoubi⁵, Samha Al Ayoubi², Beatriz G De la Torre^{6

7}, Fernando Albericio^{7

8}, Ayman El-Faham⁹

Affiliations

¹ Department of Math and Sciences, College of Humanities and Sciences, Prince Sultan University, Riyadh, Saudi Arabia.
² Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
³ Department of Chemistry, Faculty of Science, Suez Canal University, Ismaïlia, Egypt.
⁴ Cell Therapy Center, The University of Jordan, Amman, Jordan.
⁵ Department of Basic Medical Sciences, Faculty of Sciences, Yarmouk University, Irbid, Jordan.
⁶ KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP) School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
⁷ Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa.
⁸ CIBER-BBN (Networking Centre on Bioengineering, Biomaterials and Nanomedicine) and Department of Organic Chemistry, University of Barcelona, Barcelona, Spain.
⁹ Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.

Abstract

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 IC₅₀ 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 IC₅₀ of 2.66 ± 0.26 μM and 3.78 ± 0.55 μM, respectively. Interestingly, 3i showed potent EGFR inhibition, with an IC₅₀ of 34.1 nM compared to Erlotinib (IC₅₀ = 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.

Keywords: EGFR/CDK-2; anticancer profile; apoptosis; indole; pyrazolyl-s-triazine.