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. 2020 Dec 15;25(24):5949.
doi: 10.3390/molecules25245949.

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Romain Mustière  1 , Patrice Vanelle  1 , Nicolas Primas  1
Affiliations

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Romain Mustière et al. Molecules. .

Abstract

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.

Keywords: Plasmodium; SAR; kinase inhibitor; malaria; medicinal chemistry.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Flow diagram of article selection (derived from PRISMA flow diagram [19]).
Figure 1
Figure 1
Inhibitors of PfCDPK1 K252a 1 and purfalcamine 2.
Figure 2
Figure 2
Inhibitors of PfCDPK1 discovered by Lemercier et al. [28].
Figure 3
Figure 3
Best compounds, from each chemical series having a molecule with an IC50 equal to or below 20 nM toward PfCDPK1 in the screening realized by Crowther et al. [33].
Figure 4
Figure 4
4-Aminopyrazolopyrimidine and 4-aminoimidazopyrazine inhibitors of PfCDPK4. 1 On mammalian fibroblast cells. 2 On HepG2 cells.
Figure 5
Figure 5
Aminopyrazole-carboxamide and indolone inhibitors of PfCDPK4.
Figure 6
Figure 6
Hexadecyltrimethylammonium bromide 20 structure.
Figure 7
Figure 7
Hits from Crowther et al. against PfCK [46].
Figure 8
Figure 8
CX-4945, an HsCK2 inhibitor in clinical trials, also inhibits PfCK2.
Figure 9
Figure 9
Imidazopyridazines inhibitors of PfCLK1.
Figure 10
Figure 10
Molecules inhibiting PfCLK1 or PfCLK3.
Figure 11
Figure 11
Inhibitors of PfDPCK from Fletcher et al. [61]. 1 At 40 µM. EG = Early-stage Gametocytes, LG = Late-stage Gametocytes.
Figure 12
Figure 12
Chemical structure of emodin.
Figure 13
Figure 13
Inhibitors of PvGK.
Figure 14
Figure 14
Inhibitor of Pfmap-2 discovered by Brumlik et al. [77].
Figure 15
Figure 15
Inhibitors of PfMRK.
Figure 16
Figure 16
Natural quinone inhibitors of Pfnek-1. 1 4-day Peter’s test at 5 mg/kg/4 days intraperitoneal.
Figure 17
Figure 17
Starting from 67, medicinal chemistry work led to 66 which was further improved to 68. EG = Early-stage gametocytes, LG = Late-stage gametocytes. 1 mouse model, 20 mg/kg per os.
Figure 18
Figure 18
Aminopyrazines derivatives used to study a sulfoxide-to sulfone produg approach.
Figure 19
Figure 19
1,5-naphthyridines as inhibitors of PfPI4K.
Figure 20
Figure 20
2-chloro-3-sulfonamide pyridines as inhibitors of PfPI4K.
Figure 21
Figure 21
Inhibitors of PfPK5 discovered by Eubanks et al. [95].
Figure 22
Figure 22
Molecules inhibiting PfPK6 discovered by Crowther et al. [33].
Figure 23
Figure 23
Imidazopyridazine inhibitors of PfPK7.
Figure 24
Figure 24
Hits inhibiting PfPK7 discovered by Merckx et al. and Klein et al. [102,103].
Figure 25
Figure 25
Pyrazolopyridine 90 as inhibitor of PfPKG.
Figure 26
Figure 26
Trisubstituted pyrrole as inhibitor of PfPKG.
Figure 27
Figure 27
Trisubstituted thiazoles as inhibitors of PfPKG.
Figure 28
Figure 28
Trisubstituted isoxazole and imidazole as inhibitors of PfPKG.
Figure 29
Figure 29
α-thymidine urea analogs as inhibitors of PfTMK.
Figure 30
Figure 30
Cyclopentene analogs of thymidine as inhibitors of PfTMK.
Figure 31
Figure 31
Mutagenesis Index Score graph with protein kinases described in the review highlighted. All P. falciparum genes were ordered from the lowest to the highest score and then attributed an arbitrary rank number to obtain this curve. Data from Zhang et al. [124].
See this image and copyright information in PMC

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