Anti-HIV activity and mechanism of action of macrocyclic diamide SRR-SB3.
The importance of cyclic compounds as anti-cancer and anti-viral agents has been recognized for some time. We have studied a series of macrocyclic amide derivatives for activity against HIV infection of T lymphocytes in-vitro. Compounds containing aromatic rings and sulphur atoms were generally active, however the selectivity was greatly enhanced when two benzene rings were bridged by a disulphide linkage to produce 7-methyl-6,7,8,9-tetrahydrodibenzo[c,k][1,2,6,9]-dithiadiazacyc lododecine-5,10-dione (SRR-SB3). This compound was studied in detail with different cell and virus infections including macrophages and chronically infected H9 cells. It was active with an EC50 (the dose affording 50% inhibition of infection) of 0.05-01 microg mL(-1) and a TC50 (concentration reducing uninfected cell growth by 50%) of 50 microg mL(-1). The compound did not inhibit protease, but seemed to act by inhibiting maturation of progeny virus, by interfering with precursor protein processing. It was synergistic with AZT (3'-azido-3'-deoxythymidine; zidovudine) when tested in-vitro. The unusual mode of action and potent anti-HIV activity in T lymphocytes and macrophages makes this compound a potential candidate for clinical trials.
The Centre for Bioactivity Screening of Natural Products, Department of Pharmacy, King's College London, UK.
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N
Mahmood
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Jhaumeer-Lauloo
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Sampson
P J
PJ
Houghton
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D004220:Disulfides / Q000494:pharmacology*; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D001549:Benzamides; D004220:Disulfides; C105415:SRR SB3; D015215:Zidovudine