Synthesis and anti-HIV activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulfonamide and its derivatives

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Abstract

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene) amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its derivatives were synthesized by reaction of isatin and its derivatives with sulphadimidine. Their chemical structures have been confirmed by IR, 1H NMR data and elemental analysis. Investigation of anti-HIV activity of compounds were tested against replication of HIV-1 (IIIB) and HIV-2 (ROD) strains in acutely infected MT-4 cells and the activity compared with standard azidothymidine. Among the compounds tested, 4-[(1,2-dihydro-2 oxo-3H-indol-3-ylidene)amino]-N(4,6-dimethyl-2-pyrimidinyl)-benzene sulphonamide and its N-acetyl derivative were the most active compounds.

Introduction

Acquired immunodeficiency syndrome (AIDS) is a fatal pathogenic disease caused by a retrovirus, human immunodeficiency virus (HIV). HIV binds to CD-4 receptor of human T lymphocytes and induces cytotoxicity, which leads to immunodeficiency. Human T lymphocytes (MT-4 cells) are targets for HIV replication, and MT-4 cell line used for the screening of anti-HIV agents (Pauwels et al., 1987). Currently MT-4 cells are also used for in vitro evaluation of combination therapy for the treatment of HIV (Witvrouw et al., 2000). In recent years, much attention has been devoted in the search for effective chemotherapeutic agents of inhibition for replication of HIV. The new indole derivative, delavirdine has been approved for the treatment of AIDS (Romero, 1994).

Isatin (2,3-dioxo indole) is a versatile lead molecule for designing of potential antiviral agents. The first clinically approved anti-viral agent, Methisazone, was used for the treatment of smallpox and variola viral infection (Bauer and Sadler, 1960). Thiosemicarbazone derivatives of isatin were tested for the inhibition of HIV nucleoprotein synthesis (Teitz et al., 1994). Mannich bases of isatin derivatives were screened for anti-HIV activity against HIV-1 and HIV-2 in acutely infected MT-4 cells, and one of the derivative showed significant activity against HIV-1 (Pandeya et al., 1998). The titled compounds were synthesized by reacting isatin and its derivatives with sulphadimidine. The synthesized compounds were tested for anti-HIV activity against replication of HIV-1 (III B) and HIV-2 (ROD) in MT-4 cells, and compared with a standard antiviral agent, azidothymidine (AZT).

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Chemistry

Melting points were determined using an open-ended capillary tube method and are uncorrected. The purity of the synthesized compounds were checked by TLC. UV spectra were taken in a Hitachi 2000 series UV Spectrophotometer and FT-IR recorded on a Perkin-Elmer 1605 series FT-IR in a KBr disc. 1H NMR spectra were recorded at 300 MHz on a Bruker FT-NMR spectrophotometer using TMS as internal standard. Mass spectra on a Varian Atlas CH-7 Mass Spectrophotometer at 70 eV and elemental analysis were

Results

Effective concentration (EC50) of synthesized compounds on HIV-1 and HIV-2 replications were measured by the inhibition of virus induced cytopathic effect in MT-4 cells. Cytotoxicity (CC50) of test compounds in mock infected MT-4 cells was also measured by MTT-method. Anti-HIV activity and cytotoxicity of test compounds were compared with standard AZT against the replication of HIV-1 and HIV-2 in acutely infected MT-4 cells. Effective concentration for inhibition of replication of HIV-1 ranges

Discussion

N-Methyl isatin-β-4′:4′-diethyl thiosemicarbazone and N-allyl isatin-β-4′:4′-diallylthiosemicarbazone were tested to confirm the inhibition of HIV (HTLV-1) replication (Teitz et al., 1994). Schiff and Mannich bases of isatin derivatives were synthesized and evaluated for the anti-HIV activity against HIV-1 and HIV-2 in MT-4 cells. Some of their derivatives showed significant activity against the replication of HIV-1 (Pandeya et al., 1999a, Pandeya et al., 1999b, Pandeya et al., 1999c, Pandeya

Acknowledgements

The authors would like to express their gratitude and thanks to the Professor E. De Clercq, Rega Institute for Medical Research, Belgium for anti-HIV screening.

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