Design, synthesis and biological evaluation of functionalized phthalimides: A new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite

Singh, Anil Kumar; Rajendran, Vinoth; Pant, A.K.; Ghosh, Prahlad C.; Singh, Neelu; Narayanan, Latha; Garg, Suresh; Pandey, Kailash C.; Singh, Brajendra K.; Rathi, Brijesh

doi:10.1016/j.bmc.2015.02.029

Cited by 43 publications

(25 citation statements)

References 35 publications

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“…Phthalimide (Pht) skeleton is an imperative nucleus for various bioactive molecules 14 – 17 , starting material for alkaloids, pharmacophores 18 , 19 and antimalarials 20 . We also recently reported Pht analogues tailored with cyclic amines as moderate inhibitors of P. falciparum 21 , 22 . The presence of additional high-valued bioactive heterocycles may intensify the efficacy of the Phts.…”

Section: Introductionmentioning

confidence: 99%

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

Kumar

Achieng

Rajendran

et al. 2017

Sci Rep

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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.

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Section: Introductionmentioning

confidence: 99%

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

Kumar

Achieng

Rajendran

et al. 2017

Sci Rep

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“…Six compounds showed inhibitory activity, and two of them (No. 14 and 24) were identified as potent anti-malarial agents against chloroquine resistant strains [112] .…”

Section: Pure and Synthesized Compounds A) Sole Inhibitors For Fpsmentioning

confidence: 99%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

Abaza

2019

Parasitologists United Journal

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“…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]. Encouraged by this, and with a view to discovering new anti-schistosomiasis agents, we employed the Pht synthon to perform the synergistic fusion of highly-valued heterocyclic scaffolds that included the benzimidazole and triazole moieties.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µM against both somules and adults (6d, 6f, 6i-6l, 6n-6p, 6s, 6r', 6t' and 6w). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (6l, 6d, 6f, 6r' and 6s) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC 50 values ≥50 µM). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.

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Design, synthesis and biological evaluation of functionalized phthalimides: A new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite

Cited by 43 publications

References 35 publications

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

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

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

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

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