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.

Background/Objectives: Malaria is a tropical disease mainly caused by Plasmodium falciparum and represents a global public health problem, with over 200 million cases and 500 thousand deaths reported worldwide. Considering its treatment limitations, it is essential to develop new compounds against malaria. In this context, acridine derivatives are privileged structures. Methods: Thus, new spiroacridines containing N-acylhydrazone (AMTAC) and N-phenylacetamide (ACMD) were synthesized and evaluated in malaria and cytotoxicity assays, as well as in silico studies. Results: As a result, five spiroacridines showed inhibitory activity over 70% against the P. falciparum 3D7-GFP strain at 10 μM, along with an IC₅₀ range of 2–4 μM. After a brief Structure–Activity Relationship (SAR) analysis, it was observed that the spiroacridine structure must be associated with the hydrazone moiety to successfully inhibit parasite growth. In addition, these molecules presented promising resistance profile, with selectivity for the parasite. After computational studies, spiroacridines showed better affinity with dihydrofolate reductase (DHFR), overcoming the quadruple mutant resistance to pyrimethamine, with more stability in complex with the enzyme. Conclusions: Therefore, the potential of spiroacridines against malaria, with moderate resistance and selectivity profile, as well as DHFR inhibition greater than pyrimethamine, was confirmed.

O câncer, doença proliferativa de caráter progressivo e letal possui estimativas de que até 2050 ocorra o surgimento de 35 mil novos casos. Na expectativa de frear esse panorama, derivados 9-aminoacridínicos, como o ACS-AZ-10, demonstram atividade antiangiogênica. Dessa forma, o objetivo desse trabalho é elucidar o mecanismo de ação antiangiogênica, perfil farmacocinético e teoria do funcional da densidade do ACS-AZ-10. Para isso, após desenhar e minimizar a estrutura (MarvinSketch e ArgusLab, respectivamente), a validação (RMSD inferior a 2,0 Å) e o docking molecular foram realizados no GOLD com o receptor do fator de crescimento endotelial vascular 2 (VEGFR-2) (PDB ID: 4AGD). As interações foram visualizadas no Discovery Studio. O perfil farmacocinético foi avaliado no SwissADME e XenoSite. A ancoragem foi validada com RMSD (ASP) de 1,98 Å e o ACS-AZ-10 apresentou afinidade promissora pelo domínio quinase do receptor VEGFR-2, (fitscore = 36,45), superior ao obtido pelo ligante co-cristalizado (fitscore = 35,37). Foram observadas ligações de hidrogênio com Leu840 e Asn923 e interação carbono-hidrogênio com Gly922. Cabe destacar que as interações com Cys919, Glu917, Lys868 e Leu840 foram consideradas fundamentais para a atividade catalítica da quinase. Quanto à farmacocinética, o composto demonstrou alta absorção gastrointestinal e não apresentou violações quanto às regras de druglikeness. Farmacocineticamente, apresenta possibilidade de sofrer N-desalquilação, na amina terciária. Há forte possibilidade de interação com DNA e proteínas no nitrogênio adjacente ao carbono 9 da acridina e com o C sp2 ligado ao benzeno. Em termos de reatividade eletrônica, os dados de DFT apontam energia total de –1887,388 kcal/mol, porém com menor reatividade global quando comparado ao ligante, conforme indicado pelo maior gap HOMO–LUMO (2,957 eV) e menor suavidade química, evidenciando regiões nucleofílicas e eletrofílicas bem definidas. O alto potencial de ionização (5,397 eV) sugere resistência a processos oxidativos e menor risco de formação de espécies reativas, embora também possa limitar interações com resíduos eletrofílicos no sítio ativo. Portanto, ACS-AZ-10 demonstrou ser um composto promissor por meio de inibição de angiogênese, associada à alta afinidade com o receptor VEGFR-2, e perfil farmacocinético com boa absorção gastrointestinal e possível metabolização por mecanismos comuns de eliminação de fármacos.