Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti and Chiara Borsari*,
{"title":"发现作为广谱抗寄生虫药物的 1,3,4-恶二唑衍生物。","authors":"Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti and Chiara Borsari*, ","doi":"10.1021/acsinfecdis.4c00181","DOIUrl":null,"url":null,"abstract":"<p >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 <i>Trypanosoma brucei</i> (<i>T. brucei</i>) and identifying a 1,3,4-oxadiazole derivative (<b>19</b>) as anti-<i>T. brucei</i> hit with predicted blood–brain barrier permeability. Subsequently, extensive structure–activity–relationship studies around the lipophilic tail of <b>19</b> led to a potent antitrypanosomal and antimalarial compound (<b>27</b>), with moderate potency also toward <i>Leishmania infantum</i> (<i>L. infantum</i>) and <i>Leishmania tropica</i>. In addition, we discovered a pan-active antiparasitic molecule (<b>24</b>), showing low-micromolar IC<sub>50</sub>s toward <i>T. brucei</i> and <i>Leishmania</i> spp. promastigotes and amastigotes, and nanomolar IC<sub>50</sub> against <i>Plasmodium falciparum</i>, 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 <b>24</b> and <b>27</b>, bearing the 1,3,4-oxadiazole privileged scaffold, as broad-spectrum low-toxicity agents for the treatment of VBPDs. An alkyne-substituted chemical probe (<b>30</b>) was synthesized and will be utilized in proteomics experiments aimed at deconvoluting the mechanism of action in the <i>T. brucei</i> parasite.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents\",\"authors\":\"Alexandra Ioana Corfu, Nuno Santarem, Sara Luelmo, Gaia Mazza, Alessandro Greco, Alessandra Altomare, Giulio Ferrario, Giulia Nasta, Oliver Keminer, Giancarlo Aldini, Lucia Tamborini, Nicoletta Basilico, Silvia Parapini, Sheraz Gul, Anabela Cordeiro-da-Silva, Paola Conti and Chiara Borsari*, \",\"doi\":\"10.1021/acsinfecdis.4c00181\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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 <i>Trypanosoma brucei</i> (<i>T. brucei</i>) and identifying a 1,3,4-oxadiazole derivative (<b>19</b>) as anti-<i>T. brucei</i> hit with predicted blood–brain barrier permeability. Subsequently, extensive structure–activity–relationship studies around the lipophilic tail of <b>19</b> led to a potent antitrypanosomal and antimalarial compound (<b>27</b>), with moderate potency also toward <i>Leishmania infantum</i> (<i>L. infantum</i>) and <i>Leishmania tropica</i>. In addition, we discovered a pan-active antiparasitic molecule (<b>24</b>), showing low-micromolar IC<sub>50</sub>s toward <i>T. brucei</i> and <i>Leishmania</i> spp. promastigotes and amastigotes, and nanomolar IC<sub>50</sub> against <i>Plasmodium falciparum</i>, 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 <b>24</b> and <b>27</b>, bearing the 1,3,4-oxadiazole privileged scaffold, as broad-spectrum low-toxicity agents for the treatment of VBPDs. 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Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents
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 IC50s 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.
期刊介绍:
ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to:
* Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials.
* Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets.
* Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance.
* Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents.
* Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota.
* Small molecule vaccine adjuvants for infectious disease.
* Viral and bacterial biochemistry and molecular biology.