Multitarget Compounds for Neglected Diseases: A Review.

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multi-target compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justi-fied by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multi-target potential of phenolic compounds was observed in all diseases under study, with the mecha-nisms related to the nucleus and transcription being the most reported mechanisms. From this per-spective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

Inhibition of the morphological transition of Candida spp. by riparins I-IV.

Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.

In vitro and ex vivo antibiofilm activity of riparin 1, and its nor and dinor homologs, against dermatophytes.

Dermatophytosis is one of the most frequent superficial mycoses in the world. They are mainly caused by the dermatophytes Trichophyton rubrum and Microsporum canis. Biofilm production is an essential factor in the pathogenesis of dermatophytes; it confers drug resistance and significantly impairs antifungal effectiveness. Therefore, we evaluated the antibiofilm activity of an alkamide-type alkaloid called riparin 1 (RIP1) against clinically relevant dermatophytes. We also produced synthetic nor (NOR1) and dinor (DINOR1) homologs for pharmacological evaluation, with a 61-70% yield. We used in vitro (96-well polystyrene plates) and ex vivo (hair fragments) models to verify the effects of these compounds on the formation and viability of biofilms. RIP1 and NOR1 showed antifungal activity against strains of T. rubrum and M. canis, but DINOR1 showed no significant antifungal activity against the dermatophytes. Furthermore, RIP1 and NOR1 significantly reduced the viability of biofilms in vitro and ex vivo (P < 0.05). RIP1 was more potent than NOR1, possibly due to the distance between the p-methoxyphenyl and the phenylamide moieties in these compounds. Due to the significant antifungal and antibiofilm activities observed for RIP1 and NOR1, we suggest that they could be useful in the treatment of dermatophytosis.