Leishmaniasis is a neglected tropical disease caused by Leishmania sp. The therapeutic arsenal is reduced and limited. In this context, acridine derivatives present themselves as promising leishmanicidal compounds. This paper involved synthesizing and evaluating the antileishmanial and immunomodulatory potential of spiro-acridine derivatives. Six spiro-acridine derivatives were obtained through nucleophilic substitution reactions between the acetohydrazide/acetamide intermediates and 9-carbaldehydeacridine, followed by spontaneous cyclization. IR, NMR, and HRMS confirmed the structures. These were analyzed in vitro against L. infantum and L. amazonensis to determine anti-promastigote, anti-amastigote, and cytotoxicity effects. Immunomodulatory activity was evaluated using CBA, DCF-DA, and DAF-FM diacetate. In silico evaluation included molecular docking and dynamics. The spiro-acridines showed a wide range of anti-promastigote activities (IC₅₀ = 0.73–234.95 µM) and non-toxicity to red blood cells. AMTAC-02 and ACMD-03 demonstrated satisfactory anti-amastigote effect (IC₅₀ = 10.47–13.50 µM), low toxicity to macrophages (CC₅₀ = 27.22–569.50 µM), and cytokine and reactive species modulation. Molecular docking proposed cysteine protease B of L. amazonensis as a target, and molecular dynamics analysis highlighted the complex’s stability using RMSD, R_g, SASA, DCCM, PCA, and MM-PBSA (ΔG = −65.225 kJ/mol). Furthermore, QM-MM calculation provided the best energy for ACMD-03 (−199.30 au). Hence, AMTAC-02 and ACMD-03 demonstrated antileishmanial potential, making them promising entities for the development of leishmanicidal drug candidates.

Introduction: Malaria is a tropical disease caused by the parasite Plasmodium sp., which is considered a significant public health challenge, particularly in Africa. Among the species related to human infection, P. falciparum and P. vivax are known for their high incidence and pathogenicity. Despite several approved drugs in the treatment, the increase in resistance mechanisms is becoming increasingly prevalent, which makes the discovery of effective and safer drugs challenging. Thus, it is necessary to explore new mechanisms of action for the discovery of innovative antimalarial agents. Among the explored targets, proteases, especially subtilisin, have shown great promise in the development of new therapeutic options. Method: A narrative review was conducted using the main databases to provide critical information about the subtilisin to design antimalarial drugs. Results: Critical data were found about the isoforms of subtilisins, highlighting SUB1 and SUB2. SBDD approaches were able to show that compounds designed to target the catalytic Asp³⁷², His⁴²⁸, and Ser⁶⁰⁶, and other such Leu⁴⁶⁹, Gly⁴⁶⁷, and Asn⁵²⁰ against SUB1, presented critical results. In addition, quinoline, benzopyran, and triterpene derivatives and peptide inhibitors show their importance, and these scaffolds can be explored in further work. Conclusions: Considering the relevance of this target, this review provided insights into medicinal chemistry, the discovery of antimalarial drugs that act by inhibiting subtilisin, and promoted a promising initiative to combat malaria.