Structure Activity Relationship of N-Substituted Phenyldihydropyrazolones Against Trypanosoma cruzi Amastigotes.

Maarten Sijm,Guy Caljon,Iwan J P De Esch,Louis Maes,Geert Jan Sterk,Rob Leurs

doi:10.3389/fchem.2021.608438

Maarten Sijm, Guy Caljon + Show 4 more

Open Access

https://doi.org/10.3389/fchem.2021.608438

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Abstract

Current drugs for Chagas disease have long treatment regimens with occurrence of adverse drug effects leading to poor treatment compliance. Novel and efficacious medications are therefore highly needed. We previously reported on the discovery of NPD-0227 (2-isopropyl-5-(4-methoxy-3-(pyridin-3-yl)phenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one) as a potent in vitro inhibitor of Trypanosoma cruzi (pIC50 = 6.4) with 100-fold selectivity over human MRC-5 cells. The present work describes a SAR study on the exploration of substituents on the phenylpyrazolone nitrogen. Modifications were either done directly onto this pyrazolone nitrogen or alternatively by introducing a piperidine linker. Attention was pointed toward the selection of substituents with a cLogP preferably below NPD-0227s cLogP of 3.5. Generally the more apolar compounds showed better activities then molecules with cLogPs <2.0. Several new compounds were identified with potencies that are in the same range as NPD-0227 (pIC50 = 6.4) and promising selectivities. While the potency could not be improved, valuable SAR was obtained. Furthermore the introduction of a piperidine linker offers new opportunities for derivatization as valuable novel starting points for future T. cruzi drug discovery.

Highlights

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease
In the previous work by Sijm et al, the pyrazolone nitrogen was substituted with various-alkyl moieties resulting in the identification of NPD-0227 (3) as a potent T. cruzi inhibitor with 100-fold selectivity over human MRC-5 cells (Table 1) (Sijm et al, 2019; Sijm et al, 2020)
Our study results in valuable SAR data that has been obtained by introducing a variety of substituents on the dihydropyrazolone nitrogen atom

Summary

INTRODUCTION

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease. It is estimated that over six million people are infected worldwide, the majority in Latin-America where the parasite is endemic. (Lidani et al, 2019; WHO, 2021). After 2 months, the disease enters the chronic phase in which the parasite becomes dormant and no symptoms are observed. This dormant phase can last for over 10 years up to lifelong (Prata, 2001). As T. cruzi proceeds via a dormant intracellular form, a possible drug needs to pass several cell membranes before reaching the parasite. The second route (Route B) started with alkylation of the dihydropyrazolone 4, either using potassium carbonate to yield intermediates 11–12, or using sodium hydride to generate intermediates 13–18 These intermediates were converted to the 3-pyridinyl derivatives via a Suzuki cross coupling, yielding final compounds 20–26 (Scheme 1, Table 1). All compounds were tested for their trypanocidal activity against intracellular forms of T. cruzi (Tulahuen CL2, β-galactosidase strain (drug sensitive strain (discrete typing units, DTU VI)) as well as for cytotoxicity on MRC-5SV2 cells (human lung fibroblasts). (Blaazer et al, 2014)

RESULTS AND DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT