Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Journal of Medicinal Chemistry
R PontikisC Monneret

Abstract

A series of 33 N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1, HEPT) were synthesized and evaluated for their anti-HIV-1 activity. In particular, the influence of substitution of the terminal hydroxy group of the acyclic structure of HEPT and the structural rigidity of this side chain were investigated. Halo (7, 8), azido (9), and amino (10-15) derivatives were synthesized from HEPT via the p-tosylate derivative 6. Acylation of the primary amine 15 afforded the amido analogs 16-20. The diaryl derivatives 26-29 were prepared by reaction of HEPT, or of the 6-(2-pyridylthio) analog 23, with diaryl disulfides in the presence of tri-n-butylphosphine. Compounds 39-41, in which the N-1 side chain is rigidified by incorporation of an E-configured double bond, were obtained by palladium(0)-catalyzed coupling of several different 6-(arylthio)uracil derivatives (37, 38) with allyl acetates 33. Compounds 13, 40a,c,d,f, and 41, incorporating an aromatic ring at the end of the acyclic side chain, were found to be more potent than the known diphenyl-substituted HEPT analog BPT (2), two of them, 40c,d, being 10-fold more active.

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Citations

Jul 8, 2010·Archives of Pharmacal Research·Mohammed T Abdel-Aal
Mar 9, 2011·Journal of Medicinal Chemistry·Jing TangZhengqiang Wang
Oct 26, 2012·The Journal of Organic Chemistry·Lukiana L Anka-LuffordDaniel J Weix
Dec 5, 2013·Journal of Pharmacy & Bioallied Sciences·Chirag RamiJayshree P Parmar
Jan 11, 2000·Antiviral Chemistry & Chemotherapy·O S Pedersen, E B Pedersen
Oct 26, 2005·Antiviral Chemistry & Chemotherapy·Svjetlana PrekupecMladen Mintas
Jun 22, 2000·Biology of Reproduction·O J D'CruzF M Uckun
Dec 18, 2004·Bioorganic & Medicinal Chemistry Letters·Sanjay BajajA K Madan
Oct 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sarah N MalkowskiLarryn W Peterson
Mar 11, 2018·Biochemistry. Biokhimii︠a︡·V T Valuev-Elliston, S N Kochetkov

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