Modulation of the stacking interaction of MN4 (M=Pt, Pd, Au) complexes with tryptophan through N-heterocyclic ligands.

A survey of selected N-heterocycle ligands showed that platination of 4-N-dimethylaminopyridine (DMAP) in [Pt(dien)L](2+) (dien=diethylenetriamine) gave especially strong π-π stacking interactions with tryptophan and the tryptophan-containing C-terminal zinc finger (ZF) of the HIV (human immunodeficiency virus) nucleocapsid protein NCp7. The association constants (all at 10(3)M(-1)) were significantly stronger (25.0 and 28.1 for tryptophan and ZF respectively) than those previously measured for the purine nucleobase 9-ethylguanine (9EtG) in [Pt(dien)(9EtG)](2+) (6.88 and 7.55 for tryptophan and ZF respectively). Extension to Pd and Au complexes also confirmed the utility of DMAP in assisting stacking interactions. The results confirm the utility of a "bioinorganic" approach to targeting and inactivation of medicinal chemistry targets using the dual approach of target recognition (non-covalent) followed by target fixation (covalent).

Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives.

Quaternized chlorpromazine, triflupromazine, and promethazine derivatives were synthesized and examined as antitubercular agents against both actively growing and non-replicating Mycobacterium tuberculosis H37Rv. Impressively, several compounds inhibited non-replicating M. tuberculosis at concentrations equal to or double their MICs against the actively growing strain. All active compounds were non-toxic toward Vero cells (IC50 > 128 microM). N-Allylchlorpromazinium bromide was only weakly antitubercular, but replacing allyl with benzyl or substituted benzyl improved potency. An electron-withdrawing substituent on the phenothiazine ring was also essential. Branching at the carbon chain decreased antitubercular activity. The optimum antitubercular structures possessed N-(4- or 3-chlorobenzyl) substitution on triflupromazine.