New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase

Abstract

To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of Trypanosoma cruzi strains (NINOA and INC-5) and on J774 murine macrophages. The design of the new naphthoquinone derivatives considered the incorporation of nitrogenous fragments with different substitution patterns present in compounds with activity on T. cruzi, and, thus, 19 compounds were synthesised in a simple manner. Compounds 2e and 7j showed the lowest IC50 values (0.43 µM against both strains for 2e and 0.19 µM and 0.92 µM for 7j). Likewise, 7j was more potent than the reference drug, benznidazole, and was more selective on epimastigotes. To postulate a possible mechanism of action, molecular docking studies were performed on T. cruzi trypanothione reductase (TcTR), specifically at a site in the dimer interface, which is a binding site for this type of naphthoquinone. Interestingly, 7j was one of the compounds that showed the best interaction profile on the enzyme; therefore, 7j was evaluated on TR, which behaved as a non-competitive inhibitor. Finally, 7j was predicted to have a good pharmacokinetic profile for oral administration. Thus, the naphthoquinone nucleus should be considered in the search for new trypanocidal agents based on our hit 7j.

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

“…In general, the compounds P9 , E2 , and the control ligand in complex with Lm TIM had a fluctuating behavior that suggests a change in the initial binding position [ 38 , 39 ]. The complex with the lowest RMSD and minimal differences between oscillations has been described as the most stable [ 40 ].…”

Ligand-Based Virtual Screening and Molecular Docking of Benzimidazoles as Potential Inhibitors of Triosephosphate Isomerase Identified New Trypanocidal Agents

“…Various researchers have described interactions with residues important in the binding of compounds at the Tc TIM interface. Other interactions with Asn67, Phe75, Thr70, Glu105, and Lys113 have been reported [ 31 , 41 , 42 , 43 ].…”

“…On the other hand, only compounds BP4 and BP6 presented a cation-π interaction with Lys113 (B), whereas compound BP1 additionally had interactions with residues Glu115 (B) and Asn67 (B), which contributed to stability through hydrophobic interactions [ 43 ]. It is worth mentioning that the control ligands also presented these types of interactions with most of the residues, where Tyr102 (A), Tyr103 (A), and Ile69 (B) stand out in the ten control ligands.…”

“…L1- Tc TIM showed a fluctuation peak in RMSD values, suggesting a change in the initial binding position, outside of the interface [ 43 ]. According to the literature, high RMSD values of a complex compared to the initial framework indicate a change in the initial binding position [ 33 , 40 ].…”

“…The van der Waals (ΔEvdw) forces form the greatest contribution to the free energy of binding in the three complexes (L1– Tc TIM, BP2– Tc TIM and BP5– Tc TIM), especially with BP5. These kind of forces are more crucial than the electrostatic to determine binding [ 43 , 51 ]. The BP5– Tc TIM complex presented the most favorable binding free energy (ΔGb) (−25.68 ± 0.19 Kcal/mol), followed by L1– Tc TIM (−24.37 ± 0.21 Kcal/mol).…”