气候变化领域集成服务门户(CCPortal): Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

CCPortal

DOI	10.1021/acsinfecdis.4c00181
	Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents
	Corfu, Alexandra Ioana; Santarem, Nuno; Luelmo, Sara; Mazza, Gaia; Greco, Alessandro; Altomare, Alessandra; Ferrario, Giulio; Nasta, Giulia; Keminer, Oliver; Aldini, Giancarlo; Tamborini, Lucia; Basilico, Nicoletta; Parapini, Silvia; Gul, Sheraz; Cordeiro-da-Silva, Anabela; Conti, Paola; Borsari, Chiara
发表日期	2024
ISSN	2373-8227
英文摘要	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.
英文关键词	vector-borne parasitic diseases; human African trypanosomiasis; leishmaniasis; malaria; broad-spectrum molecules; ADME-Tox; 1,3,4-oxadiazole
语种	英语
WOS研究方向	Pharmacology & Pharmacy ; Infectious Diseases
WOS类目	Chemistry, Medicinal ; Infectious Diseases
WOS记录号	WOS:001225171200001
来源期刊	ACS INFECTIOUS DISEASES
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/300980
作者单位	University of Milan; Universidade do Porto; i3S - Instituto de Investigacao e Inovacao em Saude, Universidade do Porto; Universidade do Porto; University of Milan; University of Pisa; University of Milan
推荐引用方式 GB/T 7714	Corfu, Alexandra Ioana,Santarem, Nuno,Luelmo, Sara,et al. Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents[J],2024.
APA	Corfu, Alexandra Ioana.,Santarem, Nuno.,Luelmo, Sara.,Mazza, Gaia.,Greco, Alessandro.,...&Borsari, Chiara.(2024).Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents.ACS INFECTIOUS DISEASES.
MLA	Corfu, Alexandra Ioana,et al."Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents".ACS INFECTIOUS DISEASES (2024).