Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

• Type: Article in International Scientific Journal
• Date: 2024

Authors

Corfu, AI (Author) Other; Santarem, N (Author) Other; Luelmo, S (Author) Other; Mazza, G (Author) Other; Greco, A (Author) Other; Altomare, A (Author) Other; Ferrario, G (Author) Other; Nasta, G (Author) Other; Keminer, O (Author) Other; Aldini, G (Author) Other; Tamborini, L (Author) Other; Basilico, N (Author) Other; Parapini, S (Author) Other; Gul, S (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Conti, P (Author) Other; Borsari, C (Author) Other

Journal

Title: Acs Infectious Diseases

Vol. 10

Pages: 2222-2238

ISSN: 2373-8227

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-010-F7C

DOI: 10.1021/acsinfecdis.4c00181

Abstract (EN): Vector-borne parasitic diseases (VBPDs) pose a significant threat to public health on a global scale. Collectively, Human African Trypanosomiasis (HAT), Leishmaniasis, and Malaria threaten millions of people, particularly in developing countries. Climate change might alter the transmission and spread of VBPDs, leading to a global burden of these diseases. Thus, novel agents are urgently needed to expand therapeutic options and limit the spread of drug-resistant parasites. Herein, we report the development of broad-spectrum antiparasitic agents by screening a known library of antileishmanial and antimalarial compounds toward Trypanosoma brucei (T. brucei) and identifying a 1,3,4-oxadiazole derivative (19) as anti-T. brucei hit with predicted blood-brain barrier permeability. Subsequently, extensive structure-activity-relationship studies around the lipophilic tail of 19 led to a potent antitrypanosomal and antimalarial compound (27), with moderate potency also toward Leishmania infantum (L. infantum) and Leishmania tropica. In addition, we discovered a pan-active antiparasitic molecule (24), showing low-micromolar IC(50)s toward T. brucei and Leishmania spp. promastigotes and amastigotes, and nanomolar IC50 against Plasmodium falciparum, together with high selectivity for the parasites over mammalian cells (THP-1). Early ADME-toxicity assays were used to assess the safety profile of the compounds. Overall, we characterized 24 and 27, bearing the 1,3,4-oxadiazole privileged scaffold, as broad-spectrum low-toxicity agents for the treatment of VBPDs. An alkyne-substituted chemical probe (30) was synthesized and will be utilized in proteomics experiments aimed at deconvoluting the mechanism of action in the T. brucei parasite.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17