Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential use in Alzheimer's disease

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127404. doi: 10.1016/j.bmcl.2020.127404.

Giang Le-Nhat-Thuy ¹, Nga Nguyen Thi ², Hai Pham-The ³, Tuyet Anh Dang Thi ⁴, Huong Nguyen Thi ³, Thu Ha Nguyen Thi ⁵, Sa Nguyen Hoang ⁶, Tuyen Van Nguyen ⁷

Affiliations

1 Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam; Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam. Electronic address: lenhatthuygiang@yahoo.com.
2 Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam; Hanoi Medical College, 35 Doan Thi Diem, Dong Da, Hanoi, Viet Nam.
3 Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi, Viet Nam.
4 Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam; Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam.
5 Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam.
6 University of Khanh Hoa, 1 Nguyen Chanh, Nhatrang, Khanhhoa, Viet Nam.
7 Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam; Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam. Electronic address: ngvtuyen@hotmail.com.

PMID: 32717612 DOI: 10.1016/j.bmcl.2020.127404

Abstract

A library of twelve quinazoline-triazole hybrid compounds were designed, synthesized and evaluated as a novel class of acetylcholinesterase inhibitors to treat Alzheimer's disease (AD). The biological assay results demonstrated the ability of several hybrid compounds to inhibit AChE Enzyme (IC₅₀ range = 0.2-83.9 µM). To understand the high potential activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of quinazoline-triazole hybrid compounds. As expected, compounds 8a and 9a-b bind to both catalytic anionic site (CAS) and peripheral anionic site (PAS) in the active site of AChE Enzyme, which implicates that these compounds could act as dual binding site inhibitors. These compounds were not cytotoxic and they also displayed appropriated physicochemical as well as pharmacokinetic profile to be developed as novel anti-AD drug candidates.

Keywords

Acetylcholinesterase inhibitor; Alzheimer’s disease; Click chemistry; Hybridization; Quinazoline; Triazole.

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