Synthesis,biological evaluation and molecular docking study of 1,2,3-1H-triazoles having 4H-pyrano[2,3-d]pyrimidine as potential Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors |
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| Authors: | Nguyen Dinh Thanh Do Son Hai Nguyen Thi Thu Ha Do Tien Tung Cao Thi Le Hoang Thi Kim Van Vu Ngoc Toan Duong Ngoc Toan Le Hai Dang |
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| Affiliation: | 1. Faculty of Chemistry, VNU University of Science, 19 Le Thanh Tong, Ha Noi, Viet Nam;2. Institute of Technique in Chemistry, Biology and Security Documents (Ministry of Public Security), Cau Giay, Ha Noi, Viet Nam;3. Faculty of Chemical Technology, Viet Tri University of Industry, Tien Kien, Lam Thao, Phu Tho, Viet Nam;4. Institute for Chemistry and Materials, Military Institute of Science and Technology (Ministry of Military), Cau Giay, Ha Noi, Viet Nam;5. Faculty of Chemistry, Thai Nguyen University of Education, 20 Luong Ngoc Quyen, Thai Nguyen, Viet Nam;6. Thai Nguyen College of Education, Quang Trung, Thinh Dan, Thai Nguyen, Viet Nam |
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| Abstract: | Some heterocycles, namely 2-amino-4H-pyran-3-carbonitriles, were synthesized in a three-component reaction from substituted benzaldehydes, malononitrile, and ethyl acetoacetate. These heterocycles have been converted subsequently into 4H-pyrano[2,3-d]pyrimidine ring by ring-closing reaction with acetic anhydride in the presence of the concentrated sulfuric acid as catalyst. The successive alkylation reaction of lactam N![/>H bond on pyrimidine-4-one ring was carried out using propargylic bromide in dry acetone in the presence of anhydrous potassium carbonate. The click chemistry of 3-propargyl-4H-pyrano[2,3-<em>d</em>]pyrimidine compounds has been accomplished by reaction with tetra-<em>O</em>-acetyl-α-d-glucopyranosyl azide using the metal-organic framework Cu@MOF-5 as a catalyst in absolute ethanol. All the synthesized 1<em>H-</em>1,2,3-triazoles <strong>8a–y</strong> were screened for their <em>in vitro Mycobacterium tuberculosis</em> protein tyrosine phosphatase B (MtbPtpB) inhibition. Kinetic studies of the most active compounds <strong>8v, 8x,</strong> and <strong>8y</strong> showed their competitive inhibition toward the MtbPtpB enzyme. The detailed structure-activity relationship (SAR) <em>in vitro</em> and <em>in silico</em> studies suggested that the interaction of Arg63 amino acids with anion type of <em>para</em>-hydroxyl group <em>via</em> a salt bridge of iminium cation was essential for strong inhibitory activity against MtbPtpB.</td>
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| Keywords: | Antitubercular activity Molecular docking PtpB |
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