Synergistic blending of high-valued heterocycles inhibits growth of Plasmodium falciparum in culture and P. berghei infection in mouse model

Abstract

A series of phthalimide analogues, novelized with high-valued bioactive scaffolds was synthesized by means of click-chemistry under non-conventional microwave heating and evaluated as noteworthy growth inhibitors of Plasmodium falciparum (3D7 and W2) in culture. Analogues 6a, 6h and 6 u showed highest activity to inhibit the growth of the parasite with IC50 values in submicromolar range. Structure-activity correlation indicated the necessity of unsubstituted triazoles and leucine linker to obtain maximal growth inhibition of the parasite. Notably, phthalimide 6a and 6u selectively inhibited the ring-stage growth and parasite maturation. On other hand, phthalimide 6h displayed selective schizonticidal activity. Besides, they displayed synergistic interactions with chloroquine and dihydroartemisinin against parasite. Additional in vivo experiments using P. berghei infected mice showed that administration of 6h and 6u alone, as well as in combination with dihydroartemisinin, substantially reduced the parasite load. The high antimalarial activity of 6h and 6u, coupled with low toxicity advocate their potential role as novel antimalarial agents, either as standalone or combination therapies.

Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages

“…Six new analogs, compounds (1−6), with or without the Pht scaffold, a molecular flexibility by adopting two different types of compounds (Figure 1A), were synthesized (Figure S1). The methyl group on Pht was included to potentially increase the binding affinity with the aspartyl proteases because it modestly extends the Pht scaffold for stronger electrostatic interactions, while phenylalanine 39 and leucine 46 were selected as linkers due to their vital antimalarial role for obtaining the maximal activity and minimal cytotoxicity.…”

Microwave Assisted Reactions of Azaheterocycles Formedicinal Chemistry Applications

“…In their attempt to obtain new antimalarial compounds, Kumar et al [32] synthesized a series of new benzimidazole (38a-c) and triazole (39a-o) derivatives. The synthesis of triazoles derivatives 39a-o took place under MW irradiation (using click chemistry), which allowed for good yields and reduced reaction time (20 min).…”

Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

“…benzimidazole and triazoles, using simple and cost-effective synthetic routes. The approach was inspired by our recent results that describe a synergistic association of Pht, benzimidazole and triazoles with antiplasmodial activity at submicromolar concentrations [34]. Although of proven value as starting synthons for the construction of bioactive anti-malarial molecules, the potential of Pht analogues against the schistosome parasite is unexplored.…”

“…Likewise, N-containing heterocyclic moieties such as benzimidazole and triazole, which are found in various natural and synthetic alkaloids, also possess diverse therapeutic applications [32,33]. We have shown that Pht analogues embedded with benzimidazole and flexible triazoles are potent agents against Plasmodium falciparum (Pf 3D7) and Pf W2 malaria strains with 50% inhibitory concentration (IC 50 ) values of~0.7 µM [34]. Also, Pht analogues possessing cyclic amines such as piperazine and piperidine displayed IC 50 values of <1 µM against the Pf 7GB malaria strain [35,36].…”