Synthesis and Antiviral Activity of 6-Benzyl Analogs of 1-[(2-Hydroxyethoxy)methyl]-5-(phenylthio)thymine (HEPT) as Potent and Selective Anti-HIV-1 Agents

Abstract

Several 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1; HEPT) were synthesized and evaluated for their anti-HIV-1 activity. LDA (lithium diisopropylamide) lithiation of 5-ethyluracil derivatives 7 and 8 and subsequent reaction with an aryl aldehyde gave 6-(arylhydroxymethyl)-5-ethyluracil derivatives 9-12. 6-(Arylhydroxymethyl)-5-isopropyluracil derivatives 15-18 were prepared from the 5-isopropyl-2-thiouracil derivatives 13 and 14 by the above procedure following oxidative hydrolysis of the thione. Preparation of the target 5-alkyl-1-(alkoxymethyl)-6-benzyluracil derivatives 27-34 was carried out by acetylation of 9-14 followed by Pd-catalyzed hydrogenolysis. The 1-butyl- (37 and 39) and 1-(2-methoxyl)- (38 and 40) 5-alkyl-6-benzyluracils were synthesized by 1-alkylation of the 3-phenacyl derivatives 35 and 36 with alkyl halides followed by deprotection of the 3-phenacyl group. Compounds synthesized in this study inhibited HIV-1 replication in MT-4 cells in the submicromolar to namomolar concentration range. From this series of compounds, 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (33) was selected for clinical evaluation.

TMC125, a Novel Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor Active against Nonnucleoside Reverse Transcriptase Inhibitor-Resistant Human Immunodeficiency Virus Type 1

“…Marketed anti-HIV compounds were extracted and purified by high-pressure liquid chromatography from the commercial formulation. Emivirine was synthesized and purified according to published methods (29).…”

Non-Nucleoside Reverse Transcriptase Inhibitors: The NNRTI Boom

“…Removal of the hydroxyl group in the (2-hydroxyethoxy)methyl side chain also improved the potency (Tanaka et al, 1992b). Changing the phenylthio moiety with benzyl analogues yielded even more potent inhibitors of HIV-1 with selectivity indices of up to 130000 (Tanaka et al, 1995). After studies on pharmacokinetics and following toxicology tests, MKC-442 was selected as the candidate for clinical trials for AIDS chemotherapy (Tanaka et al, 1995).…”

“…Changing the phenylthio moiety with benzyl analogues yielded even more potent inhibitors of HIV-1 with selectivity indices of up to 130000 (Tanaka et al, 1995). After studies on pharmacokinetics and following toxicology tests, MKC-442 was selected as the candidate for clinical trials for AIDS chemotherapy (Tanaka et al, 1995). The oral bioavailability of MKC-442 in rats was 18.4% and the 50% lethal dose in rats was >2000 mg/kg (Tanaka et al, 1995).…”

Antiviral Drug Development – Success and Failure: A Personal Perspective with a Japanese Connection

“…However, they did not exhibit any anti-herpetic activity, but, unexpectedly proved active against HIV-1 [60,61]. Starting from the original HEPT, a large variety of analogues were synthesized, and from extensive mechanism-of-action studies, it became clear that they interacted specifically with the HIV-1 reverse transcriptase at an allosteric site, different from but spatially close to the catalytic site of the NRTIs [62][63][64][65][66][67][68][69]. Emivirine (MKC-442; Figure 7) [70] was the member of the HEPT series that advanced furthest, reaching Phase III clinical trials, before development was halted.…”