Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5- a ]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis.

Autor:	Monti L; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093.; Present affiliation: Imperial College London, Chemistry Department, Molecular Sciences Research Hub, 82 Wood Lane, London W12 0BZ, UK., Liu LJ; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093., Varricchio C; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF103NB, U.K., Lucero B; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093.; Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA., Alle T; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093., Yang W; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093., Bem-Shalom I; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093., Gilson M; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093., Brunden KR; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104-6323., Brancale A; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF103NB, U.K., Caffrey CR; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093., Ballatore C; Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 11. Date of Electronic Publication: 2023 Mar 11.
DOI:	10.1101/2023.03.11.532093
Abstrakt:	Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei -infected mice with tolerable doses of TPDs 3 and 4 significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of 4 at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
Databáze:	MEDLINE
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