New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations : potential for incorporation into virostatic cocktails

06 Jun 2012

Four bis(thiosemicarbazonate)gold(III) complexes (1–4) with a general formula [Au(L)]Cl {L=L1, glyoxal-bis (N4-methylthiosemicarbazone); L2, glyoxal-bis(N4-ethylthiosemicarbazone); L3, diacetyl-bis(N4- methylthiosemicarbazone); L4, diacetyl-bis(N4-ethylthiosemicarbazone)} were synthesised and screened for activity against the human immunodeficiency virus (HIV). Complexes 1–4 were characterised using 1H-NMR and IR spectroscopy; and their purity established by micronanalysis. Complex 3 inhibited viral infection of TZM-bl cells by 98% (IC50=6.8±0.6 μM) at a non toxic concentration of 12.5 μM while complex 4 inhibited infection of these cells by 72 and 98% (IC50=5.3±0.4 μM) at concentrations of 6.25 and 12.5 μMrespectively. Themechanism of inhibition of infection in TZM-bl cells is presumably as a result of the cytostatic or anti-proliferative activity that was observed for complex 4 in real time cell electronic sensing (RT-CES) and carboxyflourescein succinimidyl ester (CFSE) analysis. Treatment of T lymphocytes from HIV infected individuals with 4 decreased CD4+ T cell expression (p=0.0049) as demonstrated by multi-parametric flow cytometry without suppressing cytokine production. None of the ligands (L1–L4) demonstrated anti-viral activity, supporting the importance of metal (gold) complexation in these potential drugs. Complexes 3 and 4were shown to have ideal lipophilicity values thatwere similarwhenshake flask (0.97±0.5 and 2.42±0.6) and in silico prediction (0.8 and 1.5) methods were compared. The activity and drug-like properties of complexes 3 and 4 suggests that these novel metal-based compounds could be combined with virus inhibitory drugs to work as cytostatic agents in the emerging class of anti-HIV drugs known as virostatics.