Exploring a series of multifunctional Mn(i) tricarbonyls as prospective agents against trypanosomatid parasites: a comparative study with the Re(i) analogues

Abstract

Diseases caused by trypanosomatid parasites are among the most pressing neglected illnesses. Chagas disease, caused by Trypanosoma cruzi, and visceral Leishmaniasis, caused by Leishmania infantum, have a severe health impact in developing countries. Searching for prospective metal-based drugs against these diseases, five multifunctional fac-[Mn(CO)₃(CTZ)(NN)](PF₆) compounds, including four new derivatives, were synthesized and thoroughly characterized, featuring NN polypyridyl derivatives and Clotrimazole (CTZ) as bioactive ligands. The biological behavior was compared with that previously reported for the Re analogues. Mn compounds showed EC₅₀ values in the low micromolar range against the infective trypomastigote form of Trypanosoma cruzi and the promastigote form of Leishmania infantum and moderate selectivity indexes. While their potency against T. cruzi was comparable to the Re analogues, their selectivity was lower. Key physicochemical properties relevant to drug development were assessed: Mn(I) compounds showed lower stability in relevant tested media compared with their Re(I) counterparts and higher lipophilicity than the free ligands and the Re analogues. To gain insight into the potential mechanisms of action, the interaction with DNA and the effects on ergosterol biosynthesis in T. cruzi and L. infantum were investigated. Minimal DNA association (<1%) and moderate interaction with this target discarded DNA binding as the primary mechanism of action. In contrast, inhibition of lanosterol 14-α-demethylase (CYP51), key enzyme involved in the parasites’ ergosterol biosynthetic pathway, was experimentally confirmed. Metallomic study revealed an uptake by T. cruzi of the most promising compound, fac-[Mn(CO)₃(CTZ)(tmp)](PF₆), more than twice that of the Re(I) analogue and preferential association to soluble proteins. Proteomic analysis of T. cruzi epimastigotes treated with the Mn(I) and Re(I) analogues showed no change in CYP51 abundance, suggesting that reduced ergosterol levels may arise from post-translational modifications of the enzyme. Raman confocal microscopy allowed us to detect effects of the most promising Mn compound in treated T. cruzi. Furthermore, the photoinduced CO release properties of both Mn and Re analogues were examined, searching for an additional and yet non-studied potential mechanism of action of metal-tricarbonyls in these trypanosomatid parasites. Collectively, the results highlight the potential of Mn(I) tricarbonyls as promising candidates for further drug development.