Abstract
A dihydropyrimidine (DHPM) derivative was synthesized, characterized by
X-ray diffraction and searched in silico for its inhibitory activities
against AccD5 enzyme, the CT domain of a Mycobacterium tuberculosis
ACCase. Its molecular structure was compared to another DHPM derivative
(DHPM II). The results have shown that the (+/-)
2,6-methano-4-thioxo-3,4,5,6-tetrahydro-2H-1,3,5 benzoxadiazocines
(DHPM I) and (+/-)2,6-methano-4-oxo-3,4,5,6-tetrahydro-2H-1,3,5
benzoxadiazocines (DHPM II) belong to the monoclinic and triclinic
systems, respectively, and their crystal structures are stabilized by
N-H center dot center dot center dot O, O-H center dot center dot center
dot O and N-H center dot center dot center dot S interactions. The DHPM
derivatives established hydrogen bond interactions with the
oxyanion-stabilizing residues (Gly-434/Ala-435) beyond the Thr-217,
Phe-394 and Ile-216 in the biotin pocket. The predicted MoB of the DHPM
derivatives (21R, 24S, 22R) configuration showed that its phenyl moiety
was positioned on the interface between the biotin and propionyl-CoA
pockets, suggesting a possible blockade of both subsites. Additionally,
the hydrogen bonds involving the O-bridged phenyl ring of the DHPM
derivatives (21S, 24R, 22S) configuration with Gly434 in the
oxyanion-stabilizing region placed its phenyl moiety in the bottom of
the biotin pocket establishing hydrophobic interactions with Leu164,
Tyr167, Val459 and Ala155. These results indicate the DHPM derivatives
as potential AccD5 inhibitors and promising starting points for future
optimizations. Although the overlap of DHPM I and DHPM II did not
present significant differences, the exchange of a sulfur atom for an
oxygen atom increased the predicted biological potential.
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