- 4-Aminoquinoline derivatives: Synthesis, in?vitro and in?vivo antiplasmodial activity against chloroquine-resistant parasites
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Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in?vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in?vivo. These 4-aminoquinolines cured BALB/c mice infected with P.?berghei. The ED50values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18?mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500?mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
- Singh, Shailja,Agarwal, Drishti,Sharma, Kumkum,Sharma, Manish,Nielsen, Morten A.,Alifrangis, Michael,Singh, Ashok K.,Gupta, Rinkoo D.,Awasthi, Satish K.
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p. 394 - 407
(2016/07/15)
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- 4-amino-7-chloroquinolines: Probing ligand efficiency provides botulinum neurotoxin serotype a light chain inhibitors with significant antiprotozoal activity
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Structurally simplified analogues of dual antimalarial and botulinum neurotoxin serotype A light chain (BoNT/A LC) inhibitor bis-aminoquinoline (1) were prepared. New compounds were designed to improve ligand efficiency while maintaining or exceeding the inhibitory potency of 1. Three of the new compounds are more active than 1 against both indications. Metabolically, the new inhibitors are relatively stable and nontoxic. 12, 14, and 15 are more potent BoNT/A LC inhibitors than 1. Additionally, 15 has excellent in vitro antimalarial efficacy, with IC90 values ranging from 4.45 to 12.11 nM against five Plasmodium falciparum (P.f.) strains: W2, D6, C235, C2A, and C2B. The results indicate that the same level of inhibitory efficacy provided by 1 can be retained/exceeded with less structural complexity. 12, 14, and 15 provide new platforms for the development of more potent dual BoNT/A LC and P.f. inhibitors adhering to generally accepted chemical properties associated with the druggability of synthetic molecules.
- Opsenica, Igor M.,Tot, Miklo?,Gomba, Laura,Nuss, Jonathan E.,Sciotti, Richard J.,Bavari, Sina,Burnett, James C.,?olaja, Bogdan A.
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p. 5860 - 5871
(2013/08/23)
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