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.
Highlights
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
The drug resistance coupled with the demand of a newly accepted set of antimalarial target product profiles has prompted the search for new inexpensive and stable antimalarials with novel modes of action that can be implemented for the treatment of all malaria species
All the listed analogues were screened against chloroquine sensitive (3D7) and resistant (W2) strains of P. falciparum in culture and the lead molecules 6h and 6u displayed strong multi-stage antimalarial activity in submicromolar range
Summary
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. As a part of our ongoing efforts and diverse therapeutic efficiency of these heterocycles, we report here the design of synergistic association of Pht, benzimidazole and flexible triazoles anticipating new analogues as new entry for antimalarial chemotherapy. All the listed analogues were screened against chloroquine sensitive (3D7) and resistant (W2) strains of P. falciparum in culture and the lead molecules 6h and 6u displayed strong multi-stage (i.e. ring stage and trophozoite stages) antimalarial activity in submicromolar range. Efforts aimed at generating new antimalarial entries based on Phts was achieved through key structural variations that included the addition of benzimidazole and flexible triazoles
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