Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

• Main Authors: Darline Dize (Author), Mariscal Brice Tchatat Tali (Author), Cyrille Armel Njanpa Ngansop (Author), Rodrigue Keumoe (Author), Eugenie Aimée Madiesse Kemgne (Author), Lauve Rachel Tchokouaha Yamthe (Author), Patrick Valere Tsouh Fokou (Author), Boniface Pone Kamdem (Author), Katsura Hata (Author), Fabrice Fekam Boyom (Author)
• Format: Book
• Published: MDPI AG, 2024-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K⁺ channel blocker (E4031) were screened for their inhibitory effects on <i>Leishmania donovani</i>, <i>Plasmodium falciparum</i>, and <i>Trypanosoma brucei</i>. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against <i>L. donovani</i> promastigotes (IC₅₀: 12.4 µM), amastigotes (IC₅₀: 4.28 µM), <i>P. falciparum</i> (IC₅₀: 0.028 µM), and <i>T. brucei brucei</i> (IC₅₀: 0.81 µM). In addition, compound X inhibited the growth of <i>P. falciparum</i> (IC₅₀: 0.0052 µM) and <i>T. brucei brucei</i> (IC₅₀: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski's rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K⁺ channel blockers and DHFR inhibitors.

Item Description

10.3390/futurepharmacol4010013
2673-9879