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Structural studies on dihydropyrimidine derivatives as Mycobacterium tuberculosis coenzyme-A carboxylase inhibitors

  • Lóide O. Sallum , Jean M.F. Custodio , Allane C.C. Rodrigues , Jean F.R. Ribeiro , Beatriz P. Bezerra , Alejandro P. Ayala , Luciana M. Ramos , Ademir J. Camargo and Hamilton B. Napolitano EMAIL logo
Published/Copyright: September 27, 2019
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Zeitschrift für Kristallographie - Crystalline Materials
From the journal Zeitschrift für Kristallographie - Crystalline Materials Volume 234 Issue 10

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⋯O, O–H⋯O and N–H⋯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.

Keywords: dihydropyrimidine; molecular docking; X-ray diffraction

Acknowledgements

The authors are grateful to the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) and Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) for financial support. Also, the authors are grateful to the High Performance Computing Center of the Universidade Estadual de Goiás (UEG).

  1. Conflict of interest: The authors declare that there is no conflict of interest.

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Received: 2019-05-17
Accepted: 2019-08-25
Published Online: 2019-09-27
Published in Print: 2019-10-25

©2019 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Graphical Synopsis
  3. Inorganic Crystal Structures
  4. Stacking polytypes of mixed alkali gallides/indides A1–2(Ga/In)3 (A=K, Rb, Cs): synthesis, crystal chemistry and chemical bonding
  5. The effect of the withdrawal speed on properties of nickel oxide thin films
  6. Organic and Metalorganic Crystal Structures
  7. Structural studies on dihydropyrimidine derivatives as Mycobacterium tuberculosis coenzyme-A carboxylase inhibitors
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https://doi.org/10.1515/zkri-2019-0032
Keywords for this article
dihydropyrimidine; molecular docking; X-ray diffraction

Articles in the same Issue

  1. Frontmatter
  2. Graphical Synopsis
  3. Inorganic Crystal Structures
  4. Stacking polytypes of mixed alkali gallides/indides A1–2(Ga/In)3 (A=K, Rb, Cs): synthesis, crystal chemistry and chemical bonding
  5. The effect of the withdrawal speed on properties of nickel oxide thin films
  6. Organic and Metalorganic Crystal Structures
  7. Structural studies on dihydropyrimidine derivatives as Mycobacterium tuberculosis coenzyme-A carboxylase inhibitors
  8. Crystal and molecular structures of boldenone and four boldenone steroid esters
  9. Third-order nonlinear optical properties of three chlorinated thienyl chalcones derivatives: synthesis, structural determination and Hirshfeld surface analysis
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