The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled “Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology”.

Renin, a key aspartic protease central to the renin–angiotensin–aldosterone system (RAAS), remains a therapeutic target for hypertension despite the withdrawal of the only approved direct renin inhibitor, Aliskiren, due to unfavorable drug–drug interactions and safety concerns. Here, we report a computational protein design-driven evaluation of (S)-3-((3-(1H-imidazol-1-yl)propyl)amino)-2-(((S)-1-carboxy-2-(cyclooctanecarboxamido)ethyl)amino)-3-oxopropanoic acid (N-CDAH), a novel lipophilic cyclooctanoyl- derivative, as a next-generation renin inhibitor scaffold. This scaffold was designed based on the rationale of leveraging the carnosine like backbone while optimizing lipophilicity and metabolic stability. Pharmacokinetic, ADME, and toxicity predictions (SwissADME, pkCSM) revealed greater predicted aqueous solubility, enhanced metabolic stability, and significantly reduced off-target liabilities compared with Aliskiren (specifically, non-inhibition of major CYP isoforms). Molecular docking (AutoDock Vina binding affinity: −8.08 kcal/mol; Maestro Induced Fit Docking score: −11.149 kcal/mol) and molecular dynamics simulations confirmed favorable binding interactions, conformational adaptability, and complex stability within the renin active site. To contextualize its performance within the broader chemical space, the diastereomeric analog of N-CDAH as well as structurally related compounds identified through SwissSimilarity were also examined using computational workflow. The MD analysis (200 ns) demonstrated that the inhibitor is anchored via a dual stabilization mechanism: hydrophobic enclosure coupled with persistent ionic interactions. These integrative in silico results highlight the potential of this derivative to overcome Aliskiren’s pharmacological shortcomings, providing a strong computational rationale for experimental validation and underscoring the role of structure-based drug design in antihypertensive drug discovery.

The interaction of carnosine histidine containing dipeptide with the semiquinone radical of 3,4Dihydroxybenzoic dianion in dimethyl sulfoxide solution under aerobic conditions was investigated in the present study. The interaction of dipeptide-manganese system with the same semiquinone was also studied under the same conditions. The metal-binding and redox chemistry of these systems were investigated using electronic, ESR 1H-NMR spectroscopies and cyclic voltammetry. The in-situ formal semiquinone radicals (extensively studied in previous works) were significantly modified upon addition of carnosine, as evidenced by the redistribution of the visible absorption bands and the change of the redox couples of the catecholic product. Subsequent influence of manganese ions induced further spectral and electrochemical changes, consistent with metal centered oxidation and formation of ligand-stabilized manganese species. Paramagnetic broadening in the 1H-NMR spectra supported the presence of higher-valent manganese intermediates in solution. The combined data support a cooperative redox pathway in which semiquinone species mediate both peptide oxidation and manganese centered electron transfer. These results provide chemical insight into the understanding of multicomponent systems usually present in nature.