Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Linciano, P (Author) Other; Pozzi, C (Author) Other; dello Iacono, L (Author) Other; di Pisa, F (Author) Other; Landi, G (Author) Other; Bonucci, A (Author) Other; Gul, S (Author) Other; Kuzikov, M (Author) Other; Ellinger, B (Author) Other; Witt, G (Author) Other; Santarem, N (Author) Other; Baptista, C (Author) Other; Franco, C (Author) Other; Moraes, CB (Author) Other; Mueller, W (Author) Other; Wittig, U (Author) Other; Luciani, R (Author) Other; Sesenna, A (Author) Other; Quotadamo, A (Author) Other; Ferrari, S (Author) Other; Pohner, I (Author) Other; Anabela Cordeiro da Silva (Author) FFUP; Mangani, S (Author) Other; Costantino, L (Author) Other; Costi, MP (Author) Other

Journal

Title: Journal of Medicinal Chemistry

Vol. 62

Pages: 3989-4012

ISSN: 0022-2623

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 0 Citations

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Other information

Authenticus ID: P-00Q-GB5

DOI: 10.1021/acs.jmedchem.8b02021

Abstract (EN): 2-Amino-benzo[d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[d]thiazoles with improved enzymatic activity (TbPTR1 IC50 = 0.35 mu M; LmPTR1 IC50 = 1.9 mu M) and low mu M antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino-N-benzylbenzo[d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC50 = 7.0 mu M). Formulation of 4c with hydroxypropyl-beta-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 24