Literature DB >> 1469700

Synthesis and antiviral activity of deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents.

H Tanaka1, H Takashima, M Ubasawa, K Sekiya, I Nitta, M Baba, S Shigeta, R T Walker, E De Clercq, T Miyasaka.   

Abstract

The effect of substitution in the acyclic structure of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine (HEPT) on anti-HIV-1 activity was investigated by synthesizing a series of deoxy analogs and related compounds. Preparation of 1-[(2-alkyloxyethoxy)methyl]-6- (phenylthio)thymine (2-4) derivatives was carried out based on alkylation of HEPT with primary alkyl halides. Preparation of the 1-[(alkyloxy)methyl]-6-(phenylthio)thymine (26-31) and 1-[(alkyloxy)methyl]-6-(arylthio)-2-thiouracil (32-45) derivatives was carried out on the basis of LDA lithiation of 1-[(alkyloxy)-methyl]thymine (9-14) and 1-[(alkyloxy)methyl]-2-thiouracil (15-25) followed by reaction with diaryl disulfides. The oxidative hydrolysis of the 2-thiouracil derivatives gave 1-[(alkyloxy)methyl]-6-(arylthio)uracil derivatives (46-57). 1-Alkyl-6-(phenylthio)thymine (59-61) derivatives were prepared on the basis of alkylation of 6-(phenylthio)thymine (58). Methylation of the hydroxyl group of HEPT did not affect the anti-HIV-1 activity of HEPT. Substitution of the 1-(2-hydroxyethoxy)methyl group by ethyl, butyl, methoxymethyl, (propyloxy)methyl, and (butyloxy)-methyl groups somewhat improved the original anti-HIV-1 activity of HEPT. Substitution with ethoxymethyl and (benzyloxy)methyl groups further potentiated the activity [EC50: 1-(ethoxy-methyl)-6-(phenylthio)thymine (27), 0.33 microM; 1-[(benzyloxy)methyl]-6-(phenylthio)thymine (31), 0.088 microM]. When the 5-methyl group of 27 and 31 was replaced by an ethyl or an isopropyl group, the anti-HIV-1 activity was improved remarkably [EC50: 5-ethyl-1-(ethoxymethyl)-6-(phenylthio)-uracil (46), 0.019 microM; 5-ethyl-1-[(benzyloxy)methyl]-6-(phenylthio)uracil (52), 0.0059 microM; 5-isopropyl-1-(ethoxymethyl)-6-(phenylthio)uracil (55), 0.012 microM; 5-isopropyl-1-[(benzyloxy)methyl]-6-(phenylthio)uracil (56), 0.0027 microM]. Introduction of two m-methyl groups into the phenylthio ring also potentiated the activity.

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Year:  1992        PMID： 1469700     DOI： 10.1021/jm00103a009

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  11 in total

1.  Structure-activity correlation study of HIV-1 inhibitors: electronic and molecular parameters.

Authors:  S Hannongbua; L Lawtrakul; J Limtrakul
Journal:  J Comput Aided Mol Des       Date:  1996-04       Impact factor: 3.686

2.  Predicting anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones: computational approach using reformed eccentric connectivity index.

Authors:  Vipin Kumar; Satish Sardana; Anil Kumar Madan
Journal:  J Mol Model       Date:  2004-11-03       Impact factor: 1.810

3.  HEPT derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase: QSAR studies agree with the crystal structures.

Authors:  Anderson Coser Gaudio; Carlos Alberto Montanari
Journal:  J Comput Aided Mol Des       Date:  2002-04       Impact factor: 3.686

4.  A novel simple QSAR model for the prediction of anti-HIV activity using multiple linear regression analysis.

Authors:  Antreas Afantitis; Georgia Melagraki; Haralambos Sarimveis; Panayiotis A Koutentis; John Markopoulos; Olga Igglessi-Markopoulou
Journal:  Mol Divers       Date:  2006-08-01       Impact factor: 2.943

5.  Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives.

Authors:  Norikazu Sakakibara; Gianfranco Balboni; Cenzo Congiu; Valentina Onnis; Yosuke Demizu; Takashi Misawa; Masaaki Kurihara; Yoshihisa Kato; Tokumi Maruyama; Masaaki Toyama; Mika Okamoto; Masanori Baba
Journal:  Antivir Chem Chemother       Date:  2015-10-28

6.  Predicting anti-HIV activity: computational approach using a novel topological descriptor.

Authors:  S Gupta; M Singh; A K Madan
Journal:  J Comput Aided Mol Des       Date:  2001-07       Impact factor: 3.686

7.  Design, synthesis, and anti-HIV-1 activity of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives.

Authors:  Norikazu Sakakibara; Masanori Baba; Mika Okamoto; Masaaki Toyama; Yosuke Demizu; Takashi Misawa; Masaaki Kurihara; Kohji Irie; Yoshihisa Kato; Tokumi Maruyama
Journal:  Antivir Chem Chemother       Date:  2015-02

8.  Differential activities of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains.

Authors:  J Balzarini; M Baba; E De Clercq
Journal:  Antimicrob Agents Chemother       Date:  1995-04       Impact factor: 5.191

9.  Calculation of binding affinities of HIV-1 RT and beta-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches.

Authors:  Niall J English
Journal:  J Mol Model       Date:  2007-08-10       Impact factor: 1.810

10.  Synthesis of N-substituted 5-iodouracils as antimicrobial and anticancer agents.

Authors:  Supaluk Prachayasittikul; Nirun Sornsongkhram; Ratchanok Pingaew; Apilak Worachartcheewan; Somsak Ruchirawat; Virapong Prachayasittikul
Journal:  Molecules       Date:  2009-07-27       Impact factor: 4.411
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