Novel scaffold hopping of potent benzothiazole and isatin analogues linked to 1,2,3-triazole fragment that mimic quinazoline epidermal growth factor receptor inhibitors: Synthesis, antitumor and mechanistic analyses.

Autor: Rezki N; Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia. Electronic address: nadjetrezki@yahoo.fr., Almehmadi MA; Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia., Ihmaid S; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia., Shehata AM; Pharmacology and Toxicology Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Egypt., Omar AM; Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt., Ahmed HEA; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 11884 Nasr City, Cairo, Egypt. Electronic address: heahmad@taibahu.edu.sa., Aouad MR; Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Oct; Vol. 103, pp. 104133. Date of Electronic Publication: 2020 Jul 23.
DOI: 10.1016/j.bioorg.2020.104133
Abstrakt: A series of benzothiazole/isatin linked to 1,2,3-triazole moiety and terminal sulpha drugs 5a-e and 6a-e were synthesized and evaluated for cytotoxic activity against a panel of cancer cell lines. The novel compounds showed variable IC 50 range of activity and some of them were potent compared to reference drug. The promising compounds were subjected as postulated the mimicry proposal for quinazoline-based EGFR inhibitors for their inhibitory profile against EGFR TK enzyme. That data obtained revealed that most of these compounds were potent EGFR TK inhibitors at nanomolar concentrations. Among these, compounds 5a and 5b showed more potent activity on EGFR compared to erlotinib (IC 50 103 and 104 versus 67.6 nM). Based upon the results, molecular docking analysis was performed on EGFR receptor and proved the strong contribution of fragments; benzothiazole, isatin, and triazole to the binding ATP pocket. When these selected compounds 5a and 5b were tested in an HepG2 model, they could effectively inhibited tumor growth, strongly induced cancer cell apoptosis, and suppressed cell cycle progression leading to DNA fragmentation. Well-DMET profile of the most active derivatives was presented and compared to the reference drugs. Taken together, we introduced novel triazole-sulpha drug hybrid for the first time as EGFR inhibitors and the results of our studies indicate that the newly discovered inhibitors have significant potential for anticancer treatment.
Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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