Deposition of pentamidine analogues in the human body - spectroscopic and computational approaches.

Bis-benzamidines are a diverse group of compounds with high potential in pharmacotherapy, and among them, pentamidine is a drug of great therapeutic significance in Pneumocystis jiroveci pneumonia (PJP) prophylaxis and therapy. Pharmacokinetic properties of these cationic species such as transport, acid/base equilibria, and interactions with potential target molecules are still of interest, especially for recently designed compounds. To broaden our knowledge drug-likeness, human serum albumin binding, and acidity constants (K) were experimentally and theoretically examined for five pentamidine analogues 1 - 5 with -NH-CO-chain-CO-NH-bridges of increasing length and O, N, and S atoms in the chain. The studied analogues display very marked activity against Pneumocystis carinii without cytotoxicity that inspired us to perform an in silico analysis of their mode of action based on the hypothesis that the small DNA groove of rich in adenine-thymine pairs is their molecular target. These studies allowed us to classify them as very promising lead molecules.