Anti-HIV Activity and Mechanism of Action of Macrocyclic Diamide SRR-SB3

Abstract

Abstract 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]-dithiadiazacyclodode-cine-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—0.1 μgmL−1 and a TC50 (concentration reducing uninfected cell growth by 50%) of 50μmL−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.