Synthesis, protease inhibition, and antileishmanial activity of new benzoxazoles derived from acetophenone or benzophenone and synthetic precursors

Synthesis, protease inhibition, and antileishmanial activity of new benzoxazoles derived from acetophenone or benzophenone and synthetic precursors

This work reports the synthesis, protease inhibition, and antileishmanial activity of ten benzoxazole derivatives, which were obtained in a three-step synthetic route from 4-hydroxy-acetophenone and 4-hydroxy-benzophenone. These benzoxazoles, the synthetic intermediates, and the starting ketones wer...

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Bibliographic Details
Published in:Medicinal chemistry research Vol. 26; no. 6; pp. 1149 - 1159
Main Authors: Folquitto, Laís R. S., Nogueira, Priscila F., Espuri, Patrícia F., Gontijo, Vanessa S., de Souza, Thiago B., Marques, Marcos J., Carvalho, Diogo T., Júdice, Wagner A. S., Dias, Danielle F.
Format: Journal Article
Language:English
Published: New York Springer US 01-06-2017
Springer Nature B.V
Subjects:
Acetophenone
Amphotericin B
Benzophenone
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Intermediates
Ketones
Macrophages
Original Research
Papain
Pentamidine
Pharmacology/Toxicology
Protease
Proteinase
Serine
Synthesis
Toxicity
Trypsin
Trypsin inhibitors
Acetophenone
Proteases
Antiproteolytic activity
Benzoxazoles
Benzophenone
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Summary:This work reports the synthesis, protease inhibition, and antileishmanial activity of ten benzoxazole derivatives, which were obtained in a three-step synthetic route from 4-hydroxy-acetophenone and 4-hydroxy-benzophenone. These benzoxazoles, the synthetic intermediates, and the starting ketones were evaluated for their inhibitory effect on the activity of cysteine (papain, rCPB2.8, and rCPB3.0) and serine (trypsin) proteases. All compounds showed significant values of IC 50 against these enzymes (in the range of 0.0086–0.7612 µM for papain and 0.0075–0.5032 µM for trypsin), being more active than the standard inhibitors (1.7821 and 7.2318 µM, for E64 and TLCK, respectively). Following, all compounds were evaluated in vitro for their leishmanicidal activity against promastigote form of Leishmania amazonensis . The most active compounds were further evaluated against amastigote form and for its toxicity against murine macrophages. The benzoxazole 4d , a benzophenone derivative, and the intermediate 4-hydroxy-3-nitroacetophenone 2b showed significant antileishmanial activity (IC 50  = 90.3 µM and IC 50  = 130.9 µM, respectively) with selectivity indexes (5.22 and 18.09, respectively) compared to or better than those of two established leishmanicidal drugs, pentamidine (0.58) and amphotericin B (5.31). Graphical Abstract
ISSN:1054-2523
1554-8120
DOI:10.1007/s00044-017-1824-y