Research paper
Discovery of 6′-chloro-N-methyl-5’-(phenylsulfonamido)-[3,3′-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium

https://doi.org/10.1016/j.ejmech.2019.112012Get rights and content

Highlights

  • A novel pharmacophore based PfPI4K inhibitor CHMFL-PI4K-127 was discovered.

  • The inhibitor exhibited high selectivity against PfPI4K over human kinase.

  • The inhibitor potently inhibited a panel of drug-resistant strains of P. falciparum.

  • The inhibitor exhibited antimalarial efficacy in both blood stage and liver stage.

Abstract

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23–47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.

Introduction

Drug resistant malaria infections are still a severe threat to the public health [1]. In clinic, there is yet a great demand to seek novel chemotypes with new mechanisms of antimalaria in order to overcome the drug resistance. In recent years, new chemical entities with activity across different life cycle stages of the malaria parasite and new mechanisms of action have been identified [[2], [3], [4], [5], [6]]. Plasmodium phosphatidylinositol-4-kinase [3,6] is one of the attractive drug discovery targets due to its important roles in all stages of the Plasmodium lifecycle. In addition, it has been expected that the Plasmodium PI4K inhibitors would overcome the resistance of artemisinin and artemisinin-based combination therapies for P. falciparum malaria since they bear different inhibition mechanism [[7], [8], [9], [10]]. Plasmodium PI4K catalyzes the phosphorylation of phosphatidylinositol (PI) to produce the cellular secondary messenger phosphatidylinositol-4-phosphate (PI4P), subsequently initiating a cascade of downstream events to modulate a variety of biological processes including secondary messenger signaling, cellular membrane remodeling, and vesicular trafficking [11]. A number of Plasmodium PI4K kinase inhibitors with different chemotypes such as MMV390048 (1) [6], which is now under Phase II clinical trial [12], KAI407 (2) [13], KAI715 (3) [14], KDU731 (4) [15], KDU691 (5) [3], UCT943 (6) [16], BRD73842 (7) [17], BQR695 (8) [3], and 9 [18] have been disclosed in patents and research articles over the past several years (Fig. 1). In this study, we report the discovery of a novel bipyridine-sulfonamide chemotype PfPI4K inhibitor compound 15g (CHMFL-PI4K-127), which is obtained from optimizing a chloro-bipyridine chemotype based hit compound 15a (Fig. 2).

Section snippets

Chemistry

The synthesis of compounds 15a-g was depicted in Scheme 1. The intermediate 12a was obtained from 10a via N-Boc group protection (11a) and Miyaura borylation reaction. The pyrrolopyridine 10b was protected with acetyl chloride to give 11b, and then Miyaura borylation reaction afforded the intermediate 12b. 13 reacted with benzenesulfonyl chloride to provide sulfonamide 14, which was then converted to compounds 15a-g through Suzuki-Miyaura cross coupling reaction. As shown in Scheme 2, compounds

Conclusions

In summary, we have discovered a novel chemotype based PfPI4K kinase inhibitor compound 15g, which exhibited potent enzyme and parasite inhibitory activities. In addition, it displayed high selectivity over human lipid and protein kinases which indicated better therapeutic safety window. 15g also showed activity across a panel of clinical drug-resistant isolates and therefore might have a low risk for pre-existing cross-resistance. In the blood-stage malaria model, 15g resulted in 100%

Chemistry

All reagents and solvents were purchased from commercial sources and were used as received unless specified otherwise, or prepared as described in the literature. All moisture sensitive reactions were carried out using dry solvents under ultrapure argon protection. Glassware was dried in an oven at 140 °C for at least 12 h prior to use and then assembled quickly while hot, sealed with rubber septa, and allowed to cool under a stream of argon. Reactions were stirred magnetically using

Author contributions

The manuscript was written through contributions of all the authors. All the authors have given approval to the final version of the manuscript. X.L., Z.J., Z.H., and F.L. contributed equally to this work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant Nos, 81872745, 81773777, 81872748, 31771455, 81271863), the National Key Research and Development Program of China (Grant No. 2016YFA0400900), the Natural Science Foundation of Anhui Province (Grant No. 1908085QH348), the China Postdoctoral Science Foundation (Grant No. 2019M652057), the Frontier Science Key Research Program of CAS (Grant No. QYZDB-SSW-SLH037), the Innovative Program of Development Foundation of

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