ProTides of N-(3-(5-(2鈥?deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents

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• 作者：Christopher McGuigan^a ; ^{mcguigan@cf.ac.uk" class="auth_mail} ; Marco Derudas^a ; Blanka Gonczy^a ; Karen Hinsinger^a ; Sahar Kandil^a ; Fabrizio Pertusati^a ; Michaela Serpi^a ; Robert Snoeck^b ; Graciela Andrei^b ; Jan Balzarini^b ; Timothy D. McHugh^c ; Arundhati Maitra^d ; Ernest Akorli^d ; Dimitrios Evangelopoulos^c ; ^d ; Sanjib Bhakta^d
• 关键词：Tuberculosis (TB) ; Thymidylate synthase X (ThyX) ; Phosphate prodrugs ; Nucleoside analogues ; Anti-tuberculars
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 May, 2014
• 年：2014
• 卷：22
• 期：9
• 页码：2816-2824
• 全文大小：520 K

文摘

The flavin-dependent thymidylate synthase X (ThyX), rare in eukaryotes and completely absent in humans, is crucial in the metabolism of thymidine (a DNA precursor) in many microorganisms including several human pathogens. Conserved in mycobacteria, including Mycobacterium leprae, and Mycobacterium tuberculosis, it represents a prospective anti-mycobacterial therapeutic target. In a M. tuberculosis ThyX-enzyme inhibition assay, N-(3-(5-(2鈥?deoxyuridine-5鈥?phosphate))prop-2-ynyl)octanamide was reported to be the most potent and selective 5-substituted 2鈥?deoxyuridine monophosphate analogue. In this study, we masked the two charges at the phosphate moiety of this compound using our ProTide technology in order to increase its lipophilicity and then allow permeation through the complex mycobacterial cell wall. A series of N-(3-(5-(2鈥?deoxyuridine))prop-2-ynyl)octanamide phosphoroamidates were chemically synthesized and their biological activity as potential anti-tuberculars was evaluated. In addition to mycobacteria, several DNA viruses depend on ThyX for their DNA biosynthesis, thus these prodrugs were also screened for their antiviral properties.