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Thiazolothiazepine inhibitors of HIV-1 integrase.

Abstract：

:A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN. By contrast, compounds with a naphthalene ring system showed enhanced potency, suggesting that a hydrophobic pocket in the IN active site might accommodate an aromatic system rather than a halogen. The position of sulfur in the thiazole ring appears important for potency against IN, as its replacement with an oxygen or carbon abolished activity. Further extension of the thiazole ring diminished potency. Compounds 1, 19, and 20 showed antiviral activity and inhibited IN within similar concentrations. These compounds inhibited IN when Mn(2+) or Mg(2+) was used as cofactor. None of these compounds showed detectable activities against HIV-1 reverse transcriptase, protease, virus attachment, or nucleocapsid protein zinc fingers. Therefore, thiazolothiazepines are potentially important lead compounds for development as inhibitors of IN and HIV replication.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Neamati N,Turpin JA,Winslow HE,Christensen JL,Williamson K,Orr A,Rice WG,Pommier Y,Garofalo A,Brizzi A,Campiani G,Fiorini I,Nacci V

doi

10.1021/jm990047z

keywords:

subject

Has Abstract

pub_date

1999-08-26 00:00:00

pages

3334-41

issue

17

eissn

0022-2623

issn

1520-4804

pii

jm990047z

journal_volume

42

pub_type

杂志文章

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