Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

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.

Scheme 1

Flow diagram of article selection (derived from PRISMA flow diagram [19]).

Figure 1

Inhibitors of PfCDPK1 K252a 1 and purfalcamine 2.

Figure 2

Inhibitors of PfCDPK1 discovered by Lemercier et al. [28].

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

4-Aminopyrazolopyrimidine and 4-aminoimidazopyrazine inhibitors of PfCDPK4. ¹ On mammalian fibroblast cells. ² On HepG2 cells.

Figure 5

Aminopyrazole-carboxamide and indolone inhibitors of PfCDPK4.

Figure 6

Hexadecyltrimethylammonium bromide 20 structure.

Figure 7

Hits from Crowther et al. against PfCK [46].

Figure 8

CX-4945, an HsCK2 inhibitor in clinical trials, also inhibits PfCK2.

Figure 9

Imidazopyridazines inhibitors of PfCLK1.

Figure 10

Molecules inhibiting PfCLK1 or PfCLK3.

Figure 11

Inhibitors of PfDPCK from Fletcher et al. [61]. ¹ At 40 µM. EG = Early-stage Gametocytes, LG = Late-stage Gametocytes.

Figure 12

Chemical structure of emodin.

Figure 13

Inhibitors of PvGK.

Figure 14

Inhibitor of Pfmap-2 discovered by Brumlik et al. [77].

Figure 15

Inhibitors of PfMRK.

Figure 16

Natural quinone inhibitors of Pfnek-1. ¹ 4-day Peter’s test at 5 mg/kg/4 days intraperitoneal.

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

Aminopyrazines derivatives used to study a sulfoxide-to sulfone produg approach.

Figure 19

1,5-naphthyridines as inhibitors of PfPI4K.

Figure 20

2-chloro-3-sulfonamide pyridines as inhibitors of PfPI4K.

Figure 21

Inhibitors of PfPK5 discovered by Eubanks et al. [95].

Figure 22

Molecules inhibiting PfPK6 discovered by Crowther et al. [33].

Figure 23

Imidazopyridazine inhibitors of PfPK7.

Figure 24

Hits inhibiting PfPK7 discovered by Merckx et al. and Klein et al. [102,103].

Figure 25

Pyrazolopyridine 90 as inhibitor of PfPKG.

Figure 26

Trisubstituted pyrrole as inhibitor of PfPKG.

Figure 27

Trisubstituted thiazoles as inhibitors of PfPKG.

Figure 28

Trisubstituted isoxazole and imidazole as inhibitors of PfPKG.

Figure 29

α-thymidine urea analogs as inhibitors of PfTMK.

Figure 30

Cyclopentene analogs of thymidine as inhibitors of PfTMK.

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].