The past, present and future of anti-malarial medicines

Abstract

Great progress has been made in recent years to reduce the high level of suffering caused by malaria worldwide. Notably, the use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy (ACT) for malaria treatment have made a significant impact. Nevertheless, the development of resistance to the past and present anti-malarial drugs highlights the need for continued research to stay one step ahead. New drugs are needed, particularly those with new mechanisms of action. Here the range of anti-malarial medicines developed over the years are reviewed, beginning with the discovery of quinine in the early 1800s, through to modern day ACT and the recently-approved tafenoquine. A number of new potential anti-malarial drugs currently in development are outlined, along with a description of the hit to lead campaign from which it originated. Finally, promising novel mechanisms of action for these and future anti-malarial medicines are outlined.

Keywords: Drug development; Drug discovery; Malaria; Mechanism of action; Plasmodium.

Fig. 1

Well known anti-malarial medicines discovered between 1820 and the 1980s. Some are still used today while some have been rendered ineffective due to development of resistant strains or the emergence of undesirable side effects. Dates of first reported resistance are shown in brackets

Fig. 2

New drug combinations/formulations that have been approved for use. Brand name of the drug (in bold), partnered company (in italics) and drug combination (colour-coded to the structures) are listed

Fig. 3

Snapshot of the projects supported by MMV at different stages of the drug discovery and development pipeline (Adapted from the MMV-supported projects webpage [58])

Fig. 4

New anti-malarial compounds in development as a result of drug repurposing. Original indications for the drugs are shown in parentheses. Many of these repurposed drugs are already in Phase II trials as new potential anti-malarials

Fig. 5

New anti-malarial drug candidates that have reported no significant progress in the last 2 years. These compounds may have encountered issues during preclinical or early clinical studies

Fig. 6

Key biological and physical properties of M5717

Fig. 7

Key stages in the hit to lead pathway of M5717. Initial replacement of Br for F, replacement of pyridine with ethylpyrrolidine, and addition of a morpholine fragment led to the optimized compound M5717

Fig. 8

Key biological and physical properties of MMV253. logD and in vivo ED₉₀ kindly provided by V. Sambandamurthy, S. Hameed P. and S. Kavanagh, personal communication, 2018

Fig. 9

Key stages in the hit to lead pathway of MMV253. Initial replacement of ethylbenzene on M’1 with 2-methylpyridine resulted in lower hERG affinity and improved solubility. Substitution of the pyrrolidine in M’2 with an imidazole containing an amine spacer further improved solubility and greatly improved the potency. Addition of an N-methyl group and a cyclopropane moiety led to the optimized compound MMV253

Fig. 10

Key biological and physical properties of UCT943

Fig. 11

Key stages in the hit to lead pathway of UCT943. Initial change the phenyl substituents with a single trifluoromethyl group led to greater in vivo stability. Introduction of piperazine amide instead of methylsulfonyl and a pyrazine instead of a pyridine led to the improved solubility and potency of the optimized compound. Surprisingly, introduction of a nitrogen in the red circle resulted in complete inactivity in vivo

Fig. 12

Key biological and physical properties of AN13762. Solubility kindly provided by Y.-K. Zhang, personal communication, 2018

Fig. 13

Key stages in the hit to lead pathway of AN13762. Initial replacement of the carboxylic acid chain with a pyrazine, and subsequent switch of the ester to a substituted amide helped to improve in vivo stability and bioavailability leading to the optimized compound

Fig. 14

Key biological and physical properties of SC83288. In vivo ED₉₀ kindly provided by M. Lanzer, personal communication, 2018

Fig. 15

Key compounds in the discovery of SC83288. Initial modification of one amidino group with a sulfonamide linker (S2) resulted in improved solubility. Further modification of the remaining amidine group with substituted piperazine moieties ultimately led to the optimized compound with good solubility, permeability and high potency

Fig. 16

Key biological and physical properties of DM1157. CLint HLM and in vivo ED₉₀ kindly provided by D. Peyton, personal communication, 2018

Fig. 17

Key compounds in the discovery of DM1157. Initial combination of the reversal agent, imipramine, with the CQ core resulted in the potent RCQ compound D2. Subsequent replacement of the reversal agent with 1-(2,2-diphenylethyl)piperazine (D3), and further modification with pyridine rings led to improved potency and cLogP values for the optimized compound

Fig. 18

Key biological and physical properties of P218

Fig. 19

Key compounds in the discovery of P218. The key 2,4-diaminopyrimidine core highlighted in red can be found in a number of DHFR inhibitors

Fig. 20

Key biological and physical properties of (+)-SJ733. Sexual stage potency and logD kindly provided by K. Guy, personal communication, 2018

Fig. 21

Key stages in the hit to lead pathway of (+)-SJ733. Poor metabolic stability of the hit compound was addressed by replacement of the chloro and methoxy groups with cyano and fluoro groups respectively. Further in vivo stability and solubility improvements were made by changing the thiophene to a pyridine. Finally, the gem-dimethyl group was substituted with a trifluoromethyl group to eliminate possible metabolic oxidation

Fig. 22

Key biological and physical properties of ACT-451840

Fig. 23

Key stages in the hit to lead pathway of ACT-451840. Initial change of the n-pentyl group to an acylpiperazine (A′2) helped to improve the physicochemical properties. Subsequent introduction of a tert-butyl in place of the trifluoromethyl (A′3) and a cyano group on the southern phenyl ring resulted in the optimized compound

Fig. 24

Key biological and physical properties of OZ439. In vivo ED₉₀ kindly provided by S. Wittlin, personal communication, 2018

Fig. 25

Key stages in the hit to lead pathway of OZ439. Initial replacement of the amide linker with a phenyl ether linker resulted in improved exposure while maintaining potency (O2). The exposure was further improved by changing the alkylamine chain to a piperazine ring (O3). Final replacement of the piperazine ring with a morpholine unit led to the optimized compound OZ439, which possessed better curative efficacy in vivo

Fig. 26

Key biological and physical properties of KAF156. Solubility and logD kindly provided by T. Diagana, personal communication, 2018

Fig. 27

Key stages in the hit to lead pathway of KAF156. Potential metabolic stability issues were addressed through fluorine bioisosteres giving K2. Introduction of a dimethyl group on the piperazine ring resulted in increased potency and led to the optimized compound

Fig. 28

Key biological and physical properties of KAE609. *Significant inhibition at 50 and 500 nM doses

Fig. 29

Key stages in the hit to lead pathway of KAE609. Resolution of the initial racemic hit (K′1) gave the significantly more potent stereoisomer (K′2). Reducing the ring size further increased the potency and final halogenation of the indole ring led to the optimized compound KAE609

Fig. 30

Key biological and physical properties of DSM265

Fig. 31

Key stages in the hit to lead pathway of DSM265. Replacement of the second phenyl ring in the naphthyl group with a trifluoromethyl group improved solubility. Addition of a 1,1-difluoroethyl group significantly increased the potency and final replacement of the trifluoromethyl group in D′2 with a pentafluorosulfur moiety led to the optimized compound DSM265

Fig. 32

Key biological and physical properties of MMV048

Fig. 33

Key stages in the hit to lead pathway of MMV048. Initial replacement of the 3-methoxy-4-hydroxyphenyl moiety helped to improve in vivo stability and solubility. Further replacement of the methoxy group with a trifluoromethyl group improved potency and metabolic stability leading to the optimized compound