Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1997 Feb;41(2):385–393. doi: 10.1128/aac.41.2.385

Diarylsulfones, a novel class of human immunodeficiency virus type 1 integrase inhibitors.

N Neamati 1, A Mazumder 1, H Zhao 1, S Sunder 1, T R Burke Jr 1, R J Schultz 1, Y Pommier 1
PMCID: PMC163718  PMID: 9021196

Abstract

A majority of reported human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors are polyhydroxylated aromatic compounds containing two phenyl rings separated by aliphatic or aromatic linkers. Most inhibitors possessing a catechol moiety exhibit considerable toxicity in cellular assays. In an effort to identify nonhydroxylated analogs, a series of aromatic sulfones were tested for their ability to inhibit the 3' processing and strand transfer steps that are necessary for HIV replication. Several aromatic sulfones have previously been shown to have moderate activity against HIV-1 reverse transcriptase in cellular assays; however, their inhibitory potencies against IN have not been explored. In the present study, the inhibitory effect of a series of sulfones and sulfonamides against IN was determined. Among 52 diaryl sulfones tested, 4 were determined to be highly potent (50% inhibitory concentration [IC50], 0.8 to 10 micrograms/ml), 5 had good potencies (IC50, 11 to 50 micrograms/ml), 10 showed moderate potencies (IC50, 51 to 100 micrograms/ml), and 33 were inactive (IC50, > 100 micrograms/ml) against IN. All of the active compounds exhibited similar potencies against HIV-2 IN. Sulfa drugs, used extensively in treating Pneumocystis carinii pneumonia, a leading cause of morbidity and mortality in AIDs patients, were also examined. Among 19 sulfonamides tested, sulfasalazine (IC50, 50 micrograms/ml) was the most potent. We conclude that potent inhibitors of IN can be designed based on the results presented in this study.

Full Text

The Full Text of this article is available as a PDF (1.8 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Artico M., Silvestri R., Massa S., Loi A. G., Corrias S., Piras G., La Colla P. 2-Sulfonyl-4-chloroanilino moiety: a potent pharmacophore for the anti-human immunodeficiency virus type 1 activity of pyrrolyl aryl sulfones. J Med Chem. 1996 Jan 19;39(2):522–530. doi: 10.1021/jm950568w. [DOI] [PubMed] [Google Scholar]
  2. Burke T. R., Jr, Fesen M. R., Mazumder A., Wang J., Carothers A. M., Grunberger D., Driscoll J., Kohn K., Pommier Y. Hydroxylated aromatic inhibitors of HIV-1 integrase. J Med Chem. 1995 Oct 13;38(21):4171–4178. doi: 10.1021/jm00021a006. [DOI] [PubMed] [Google Scholar]
  3. Carteau S., Mouscadet J. F., Goulaouic H., Subra F., Auclair C. Inhibitory effect of the polyanionic drug suramin on the in vitro HIV DNA integration reaction. Arch Biochem Biophys. 1993 Sep;305(2):606–610. doi: 10.1006/abbi.1993.1468. [DOI] [PubMed] [Google Scholar]
  4. Chow S. A., Vincent K. A., Ellison V., Brown P. O. Reversal of integration and DNA splicing mediated by integrase of human immunodeficiency virus. Science. 1992 Feb 7;255(5045):723–726. doi: 10.1126/science.1738845. [DOI] [PubMed] [Google Scholar]
  5. Cushman M., Golebiewski W. M., Pommier Y., Mazumder A., Reymen D., De Clercq E., Graham L., Rice W. G. Cosalane analogues with enhanced potencies as inhibitors of HIV-1 protease and integrase. J Med Chem. 1995 Feb 3;38(3):443–452. doi: 10.1021/jm00003a007. [DOI] [PubMed] [Google Scholar]
  6. De Benedetti P. G. Molecular modeling and quantitative structure-activity analysis of antibacterial sulfanilamides and sulfones. Prog Drug Res. 1991;36:361–417. doi: 10.1007/978-3-0348-7136-5_5. [DOI] [PubMed] [Google Scholar]
  7. De Clercq E. Toward improved anti-HIV chemotherapy: therapeutic strategies for intervention with HIV infections. J Med Chem. 1995 Jul 7;38(14):2491–2517. doi: 10.1021/jm00014a001. [DOI] [PubMed] [Google Scholar]
  8. Fesen M. R., Pommier Y., Leteurtre F., Hiroguchi S., Yung J., Kohn K. W. Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. Biochem Pharmacol. 1994 Aug 3;48(3):595–608. doi: 10.1016/0006-2952(94)90291-7. [DOI] [PubMed] [Google Scholar]
  9. Hong Y. L., Hossler P. A., Calhoun D. H., Meshnick S. R. Inhibition of recombinant Pneumocystis carinii dihydropteroate synthetase by sulfa drugs. Antimicrob Agents Chemother. 1995 Aug;39(8):1756–1763. doi: 10.1128/aac.39.8.1756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Katz R. A., Skalka A. M. The retroviral enzymes. Annu Rev Biochem. 1994;63:133–173. doi: 10.1146/annurev.bi.63.070194.001025. [DOI] [PubMed] [Google Scholar]
  11. LaFemina R. L., Graham P. L., LeGrow K., Hastings J. C., Wolfe A., Young S. D., Emini E. A., Hazuda D. J. Inhibition of human immunodeficiency virus integrase by bis-catechols. Antimicrob Agents Chemother. 1995 Feb;39(2):320–324. doi: 10.1128/aac.39.2.320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Liehr J. G., Roy D. Free radical generation by redox cycling of estrogens. Free Radic Biol Med. 1990;8(4):415–423. doi: 10.1016/0891-5849(90)90108-u. [DOI] [PubMed] [Google Scholar]
  13. Lopez de Compadre R. L., Pearlstein R. A., Hopfinger A. J., Seydel J. K. A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods. J Med Chem. 1987 May;30(5):900–906. doi: 10.1021/jm00388a026. [DOI] [PubMed] [Google Scholar]
  14. Mazumder A., Gazit A., Levitzki A., Nicklaus M., Yung J., Kohlhagen G., Pommier Y. Effects of tyrphostins, protein kinase inhibitors, on human immunodeficiency virus type 1 integrase. Biochemistry. 1995 Nov 21;34(46):15111–15122. doi: 10.1021/bi00046a018. [DOI] [PubMed] [Google Scholar]
  15. Mazumder A., Neamati N., Sommadossi J. P., Gosselin G., Schinazi R. F., Imbach J. L., Pommier Y. Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase. Mol Pharmacol. 1996 Apr;49(4):621–628. [PubMed] [Google Scholar]
  16. Mazumder A., Raghavan K., Weinstein J., Kohn K. W., Pommier Y. Inhibition of human immunodeficiency virus type-1 integrase by curcumin. Biochem Pharmacol. 1995 Apr 18;49(8):1165–1170. doi: 10.1016/0006-2952(95)98514-a. [DOI] [PubMed] [Google Scholar]
  17. Mazumder A., Wang S., Neamati N., Nicklaus M., Sunder S., Chen J., Milne G. W., Rice W. G., Burke T. R., Jr, Pommier Y. Antiretroviral agents as inhibitors of both human immunodeficiency virus type 1 integrase and protease. J Med Chem. 1996 Jun 21;39(13):2472–2481. doi: 10.1021/jm960074e. [DOI] [PubMed] [Google Scholar]
  18. McMahon J. B., Gulakowski R. J., Weislow O. S., Schultz R. J., Narayanan V. L., Clanton D. J., Pedemonte R., Wassmundt F. W., Buckheit R. W., Jr, Decker W. D. Diarylsulfones, a new chemical class of nonnucleoside antiviral inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1993 Apr;37(4):754–760. doi: 10.1128/aac.37.4.754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mouscadet J. F., Carteau S., Goulaouic H., Subra F., Auclair C. Triplex-mediated inhibition of HIV DNA integration in vitro. J Biol Chem. 1994 Aug 26;269(34):21635–21638. [PubMed] [Google Scholar]
  20. Pommier Y., Kohlhagen G., Kohn K. W., Leteurtre F., Wani M. C., Wall M. E. Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8861–8865. doi: 10.1073/pnas.92.19.8861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rice P., Craigie R., Davies D. R. Retroviral integrases and their cousins. Curr Opin Struct Biol. 1996 Feb;6(1):76–83. doi: 10.1016/s0959-440x(96)80098-4. [DOI] [PubMed] [Google Scholar]
  22. Rice W. G., Bader J. P. Discovery and in vitro development of AIDS antiviral drugs as biopharmaceuticals. Adv Pharmacol. 1995;33:389–438. doi: 10.1016/s1054-3589(08)60675-4. [DOI] [PubMed] [Google Scholar]
  23. Stanwell C., Ye B., Yuspa S. H., Burke T. R., Jr Cell protein cross-linking by erbstatin and related compounds. Biochem Pharmacol. 1996 Aug 9;52(3):475–480. doi: 10.1016/0006-2952(96)00250-x. [DOI] [PubMed] [Google Scholar]
  24. Weislow O. S., Kiser R., Fine D. L., Bader J., Shoemaker R. H., Boyd M. R. New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity. J Natl Cancer Inst. 1989 Apr 19;81(8):577–586. doi: 10.1093/jnci/81.8.577. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES