تقرير
Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action
| العنوان: | Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action |
|---|---|
| المؤلفون: | de Souza, Nicolli B, Carmo, Arturene ML, da Silva, Adilson D, França, Tanos CC, Krettli, Antoniana U |
| بيانات النشر: | BioMed Central Ltd. |
| سنة النشر: | 2014 |
| المجموعة: | BioMed Central |
| مصطلحات موضوعية: | Malaria, Chloroquine analogs, Diaminealkyne, Diaminedialkyne, P. falciparum, Lactate-dehydrogenase enzyme, Docking |
| الوصف: | Background Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Methods Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro . The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human ( Hss LDH) or plasmodial lactate dehydrogenase ( Pf LDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. Results All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC 50 ) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of Pf LDH; specificity between the residues involved in H-bonds of the Pf LDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of Pf LDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC 50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei , reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. Conclusions The presence of an alkyne group and the size of the side chain affected anti- P. falciparum activity in vitro . Docking studies suggested a mechanism of action other than Pf LDH inhibition. The β-haematin assay suggested the presence of an additional ... |
| نوع الوثيقة: | report |
| اللغة: | English |
| العلاقة: | http://www.malariajournal.com/content/13/1/469Test |
| الإتاحة: | http://www.malariajournal.com/content/13/1/469Test |
| حقوق: | Copyright 2014 de Souza et al.; licensee BioMed Central Ltd. |
| رقم الانضمام: | edsbas.4C651908 |
| قاعدة البيانات: | BASE |
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