Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy

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• 作者：Ayako Hoshi^a ; Takeshi Sakamoto^a ; ^{sakamoto@josai.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Jun Takayama^a ; Meiyan Xuan^a ; Mari Okazaki^a ; Tracy L. Hartman^b ; Robert W. Buckheit Jr.^b ; Christophe Pannecouque^c ; Mark Cushman^d ; ^{cushman@purdue.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ADAM ; alkenyldiarylmethane ; NNRTI ; non-nucleoside reverse transcriptase inhibitor ; RT ; reverse transcriptase ; HIV-1 ; human immunodeficiency virus type 1 ; AIDS ; acquired immune deficiency syndrome ; ART ; antiretroviral therapy ; NRTI ; nucleoside reverse transcriptase inhibitor ; PI ; protease inhibitor ; INI ; integrase inhibitors ; FI ; fusion inhibitor ; CCR5I ; CC chemokine receptor inhibitor ; dNTPs ; deoxynucleoside triphosphate ; AZT ; azidothymidine (zidovudine) ; EDCI ; 1-(3-dimethylaminopropyl)-3-ethylc
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：24
• 期：13
• 页码：3006-3022
• 全文大小：1647 K

文摘

The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the ‘best’ one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound.