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Ukr. Bioorg. Acta 2020, Vol. 15, N1, 20-25.

5-Substituted N-(9H-purin-6-yl)-1,2-oxazole-3-carboxamides as xanthine oxidase inhibitors

Oksana V. Muzychka, Olexandr L. Kobzar, Oleg V. Shablykin, Volodymyr S. Brovarets, Andriy I. Vovk

V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine.
e-mail: vovk@bpci.kiev.ua

ABSTRACT
Synthetic 6-substituted purine derivatives are known to exhibit diverse bioactivity. In this paper, a series of N-(9H-purin-6-yl)-1,2-oxazole-3-carboxamide derivatives were synthesized and evaluated in vitro against xanthine oxidase, an enzyme of purine catabolism. The introduction of aryl substituent at position 5 of the oxazole ring was found to increase the inhibition efficiency. Some of the inhibitors containing 5-substituted isoxazole and purine moieties were characterized by IC
50 values in the nanomolar range. According to the kinetic data, the most active N-(9H-purin-6-yl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,2-oxazole-3-carboxamide demonstrated a competitive type of inhibition with respect to the enzyme-substrate. Molecular docking was carried out to elucidate the mechanism of enzyme-inhibitor complex formation. The data obtained indicate that xanthine oxidase may be one of the possible targets for the bioactive purine carboxamides.

KEYWORDS
N-(9H-purin-6-yl)-1,2-oxazole-3-carboxamides, synthesis, bioactivity, xanthine oxidase.

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