title: 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.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Hoshi
authors.affiliation: Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan. Electronic address: sakamoto@josai.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takayama
authors.affiliation: Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Xuan
authors.affiliation: Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Okazaki
authors.affiliation: ImQuestBioSciences, 7340 Executive Way, Suite R, Frederick, MD 21704, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hartman
authors.affiliation: ImQuestBioSciences, 7340 Executive Way, Suite R, Frederick, MD 21704, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.affiliation: Rega Institute for Medical Research, Katholieke, Universiteit Leuven, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue University Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, United States. Electronic address: cushman@purdue.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008697:Methane / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D004952:Esters; D018894:Reverse Transcriptase Inhibitors; D008697:Methane
keywords: ADAM; Alkenyldiarylmethane; Bioisostere; HIV-1; NNRTI; Non-nucleoside reverse transcriptase inhibitor