CHAVES, F. C. M.

NOGUEIRA, K. L.

PINTO, A. C. S.

POHLIT, A. M.

SILVA, L. F. R.

TADEI, W. P.

RCAAP - Repositório Científico de Acesso Aberto de Portugal

In vivo antimalarial activity of semi-synthetic derivates of 4-nerolidylcatechol (4-NC).

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        IN VIVO ANTIMALARIAL ACTIVITY OF SEMI-SYNTHETIC DERIVATIVES OF 4-NEROLIDYLCATECHOL (4-NC).  Nogueira KL1,2, Silva LFR1,  Pinto ACS1, Tadei WP1, Chaves FCM3, Pohlit AM1,2  1 Instituto Nacional de Pesquisas da Amazônia-INPA, Avenida André Araújo, 2936 - Petrópolis,69067-374 Manaus-AM, Brazil. 2Faculdade de Ciências Farmacêuticas da Universidade Federal do Amazonas-UFAM, Rua Alexandre Amorim, 330, Aparecida, 69010-300, Manaus-AM, Brazil. 3Empresa Brasileira de Pesquisa Agropecuária-EMBRAPA, Rodovia AM-010, Km 29, 69000-001, Manaus-AM, Brazil.  Introduction: Malaria is a tropical disease caused by parasites belonging to the genus Plasmodium. It is still one of the principal causes of morbidity and mortality worldwide despite the adoption of many control strategies that have decreased this disease [1]. Resistance to available antimalarials acquired by the parasites is a source of concern and the basis for an intense search for new classes of antimalarial compounds [2,3]. Natural products exhibiting significant antimalarial activity have been identified and semi-synthesis is an important strategy for improving physical and chemical properties and druggability in general [3]. The phenylpropanoid 4-NC is a major, unstable component obtained from Piper peltata (caapeba plant) that exhibits significant in vitro and little in vivo antimalarial activity. 4-NC derivatives exhibit greater stability and comparable in vitro antiplasmodial activity to 4-NC [4].  Methods: Diacetyl (4-NC-Ac2) and dibenzoyl (4-NC-Bz2) derivatives were obtained from 4-NC (isolated from P. peltata roots) by standard acetylation and benzoylation procedures [5]. These derivatives were tested for in vivo antimalarial activity in groups of 3 Plasmodium berghei NK65-infected female BALB/c mice treated orally and subcutaneously for 4 days at doses of 200, 400 and 600 mg/kg in the Peters suppression test [6]. Parasitemias were evaluated by optical microscopy on the 5th and 7th days. Control animals received only vehicle. The number of the protocol Ethics Committee approval was 339265. Results and Discussion: 4-NC-Ac2 [600 mg/kg/day, orally and subcutaneously] exhibited the greatest suppression of parasitemia on day 5 (64 and 72%, respectively) and day 7 (56 and 70%, respectively) and was active at doses of 50 mg/kg/day. At the highest dose, 4-NC-Bz2 [200 mg/kg/day, orally and subcutaneously] inhibited parasitemia by 46 and 48%, respectively, on day 5 and by 28 and 17%, respectively, on day 7. Its day 5 oral parasitemia suppression was greater than that of 4-NC. Diacetyl moieties confer greater chemical stability to 4-NC-Ac2 compared to 4-NC and significantly increase comparative in vivo antimalarial activity. 4-NC-Bz2 suppressed parasitemias less than 4-NC-Ac2. No toxicity related deaths or other signs of intoxication were observed. Was used as positive control Chloroquine [10 mg/kg] suppression of 100% and 99% by oral and subcutaneous administration, respectively on day 5 and 99% on day 7, DMSO 5% as vehicle offered no suppression. Conclusion: 4-NC derivatives exhibit antimalarial potential and more study is necessary to establish structure-antimalarial activity relations.  Acknowledgements: INPA, UFAM, EMBRAPA, FAPEAM, CNPq. References: 1. Walker. et al. Medicine, 42:100, 2014. 2. Schuck. et al. Eur. J. Med. Chem., 78: 375, 2014. 3. Cruz. et al. Malar. J., 12: 168, 2013. 4. Silva et al. Phytother. Res., 25: 1181, 2011. 5. Pinto. et al. Eur. J. Med. Chem., 44:2731, 2009. 6. Peters. Exp. Parasitol., 17:80, 1965. 

In vivo antimalarial activity of semi-synthetic derivates of 4-nerolidylcatechol (4-NC).

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