Benzophenone Derivatives: A Novel Series of Potent and Selective Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Abstract

A series of benzophenone derivatives has been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (RT) and the growth of HIV-1 in MT-4 cells. Through the use of the structure-activity relationships within this series of compounds and computational chemistry techniques, a binding conformation is proposed. The SAR also indicated that the major interactions of 1h with the RT enzyme are through hydrogen bonding of the amide and benzophenone carbonyls and pi-orbital interactions with the benzophenone nucleus and an aromatic function separated from the benzophenone by a suitable spacer group. The crystal structure of compound 1h has been determined. A number of compounds with potent inhibitory activity against HIV-1 RT and HIV in cellular assays at levels comparable with AZT and our efforts to identify a metabolically stable analogue are described.

Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

“…40 Benzopheneone NNRTIs 1, 2, 3, and the latter's prodrug 4 were synthesized and characterized as reported in earlier papers. [23][24][25][26] Anti-HIV-1 Activity and Resistance Profile of 1 in Cell Culture Systems. The anti-HIV-1 activity of the prototype benzophenone 1 was tested against a wider panel of mutant viruses than previously reported 23 using the methods described in earlier studies.…”

Design, synthesis, characterization, and antibacterial activity of {5-chloro-2-[(3-substitutedphenyl-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanones

“…A literature survey has revealed that benzophenone derivatives are associated with potent biological activities, such as, inhibition of HIV-1 reverse transcriptase RT [11], anticancer [12] and anti-inflammatory [13]. Benzophenones and their analogues are usually obtained from natural products [14] or by synthetic methods [15].…”

Bent Pseudoknots and Novel RNA Inhibitors of Type 1 Human Immunodeficiency Virus (HIV-1) Reverse Transcriptase

“…However, their cytotoxicity is a serious clinical concern, and the appearance of drug-resistant strains rapidly diminishes their effectiveness (Iversen et al, 1996, and references therein). The potential utility of additional inhibitors of HIV RT has fuelled an energetic search for anti-RT drugs Kang & Wang, 1994;Maruenda & Johnson, 1995;Ren et al, 1995;Wyatt et al, 1995) and antagonists of other targets (Jungheim et al, 1996;Bilello et al, 1995;Markowitz et al, 1995).…”