Monodentate Phosphine Modulation in Cyclometallated Platinum(II) Complexes for Antileishmanial, Antiviral, and Antitumor Applications

Complexes are emerging as promising alternatives for the treatment of neglected parasitic and viral infections, which urgently require new therapeutic strategies due to limited effective drugs. In this study, a series of [Pt(II)(phpy)(PR₃)Cl] complexes, where phpy is 2-phenylpyridine, and PR₃ represents triphenylphosphine (PPh₃), 1,3,5-triaza-7-phosphaadamantane (PTA), para-benzoic acid-diphenylphosphine (PPh₂(Php-COOH), or tris(2-carboxyethyl)phosphine (TCEP), are synthesized and systematically evaluated for their chemical properties and in vitro biological activities. Chemical reactivity, including ligand exchange with L-histidine and N-acetylcysteine, hydrophilic/lipophilic balance, and interactions with bovine serum albumin (BSA) and DNA, was correlated with biological outcomes. The novel TCEP complex exhibited exceptional chloride stability and intrinsic fluorescence but lacked antiviral and antileishmanial activity. The PTA derivative showed selective antileishmanial activity, achieving a selectivity index (SI) of 10.8 and reducing the infectivity index by 40% at 12 µM. Also, PTA showed selective antitumor activity in ovarian cancer (SI 9.1). In contrast, the PPh₂(Php-COOH) derivative demonstrated significant antiviral activity, inhibiting Mayaro virus and Zika virus replication by 94% and 78%, respectively, at 50 µM. These findings underscore the potential of coordination chemistry to fine-tune biological activity and support the rational design of metal-based therapeutics for neglected diseases.