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. 2021 Sep 17:9:725892.
doi: 10.3389/fchem.2021.725892. eCollection 2021.

Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations

Jonathan Rock  1 , Daniel Garcia  1 , Omar Espino  1 , Shaila A Shetu  1 , Manuel J Chan-Bacab  2 , Rosa Moo-Puc  3 , Navin B Patel  4 , Gildardo Rivera  5 , Debasish Bandyopadhyay  1   6
Affiliations

Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations

Jonathan Rock et al. Front Chem. .

Abstract

World Health Organization (WHO) identified twenty tropical disease categories as neglected tropical diseases (NTDs). Chagas' disease (also known as American trypanosomiasis) and leishmaniasis are two major classes of NTDs. The total number of mortality, morbidity, and disability attributed each year due to these two categories of diseases in magnitudes is much higher than the so-called elite diseases like cancer, diabetes, AIDS, cardiovascular and neurodegenerative diseases. Impoverished communities around the world are the major victim of NTDs. The development of new and novel drugs in the battle against Chagas' disease and leishmaniasis is highly anticipated. An easy and straightforward on-water green access to synthesize benzopyrazines is reported. This ultrasound-assisted procedure does not require any catalyst/support/additive/hazardous solvents and maintains a high atom economy. A series of eleven benzopyrazines has been synthesized, and most of the synthesized compounds possess the drug-likeness following Lipinski's "Rule of 5". Benzopyrazines 3 and 4 demonstrated moderate leishmanicidal activity against L. mexicana (M378) strain. The selective lead compound 1 showed good leishmanicidal, and trypanocidal activities (in vitro) against both L. mexicana (M378) and T. cruzi (NINOA) strains compared to the standard controls. The in vitro trypanocidal and leishmanicidal activities of the lead compound 1 have been validated by molecular docking studies against four biomolecular drug targets viz. T. cruzi histidyl-tRNA synthetase, T. cruzi trans-sialidase, leishmanial rRNA A-site, and leishmania major N-myristoyl transferase.

Keywords: ecofriendly6; leishmanicidal2; on-water7; quinoxalines5; small molecule inhibitors4; trypanocidal1; trypanosoma cruzi3.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Representative examples of naturally occurring bioactive benzopyrazines.
SCHEME 1
SCHEME 1
Ultrasound-assisted on-water green synthesis of diverse benzopyrazines.
FIGURE 2
FIGURE 2
(A) The binding mode of the interactions between 1 with T. cruzi Histidyl-tRNA synthetase (PDB ID: 4YPF). (B) Results of the validation of 1 inside the T. cruzi histidyl-tRNA synthetase active sites.
FIGURE 3
FIGURE 3
(A) The binding mode of the interactions between 1 with T. cruzi trans-sialidase (PDB ID: 1S0J). (B) Results of the validation of 1 inside the T. cruzi trans-sialidase active sites.
FIGURE 4
FIGURE 4
(A) The binding mode of the interactions between 1 with Leishmanial rRNA A-site (PDB ID: 4K32). (B) Results of the validation of 1 inside the Leishmanial rRNA A-site active sites.
FIGURE 5
FIGURE 5
(A) The binding mode of the interactions between 1 with Leishmania major N-myristoyltransferase (PDB ID: 6QDA). (B) Results of the validation of 1 inside the Leishmania major N-myristoyltransferase active sites.
FIGURE 6
FIGURE 6
X-ray crystallographic structure (ORTEP) of Compound 2. Thermal ellipsoids are shown with 50% probability.
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