Síntese, atividades antimalárica e citotóxica in vitro de híbridos 1,2,3-triazólicos-1,4-dissubstituídos inéditos derivados de diterpenos caurânicos e da 4,7-dicloroquinolina.

Abstract

The antimalarial drugs presently available in the market are disclosing limitations in the fight against this disease. Plasmodium falciparum, the main aethiological agent of human malaria, is becoming resistant to the most frequently used antimalarial drugs what makes the treatment more difficult and expensive and, therefore, RD&I of new antimalarial drugs becomes an urgent necessity. Syntheses of hybrid molecules with a triazol unity have been described disclosing promising results what is estimulating the exploration of this strategy in the quest of new antimalarial agents. In this strategy, that is called “molecular hybridization”, two bioactive chemical sructures are combined, generally by a covalent linkage, leading to a new bioactive compound. This strategy was explored in the present work and this thesis reports the syntheses of 1,2,3-triazol hybrid molecules using naturally occurring kaurane diterpenes and 4,7-dichloroquinoline, a commercial product, as starting materials to afford new potential antimalarials. Kaurenoic and xylopic acids were isolated from Wedelia paludosa (Asteraceae) and Xylopia frutescens (Annonaceae), respectively. A first series was derived from diterpene propagilic ethers which by "click" reations with different organic azides afforded the hybrid triazoles. This series led to 16 compounds including synthetic intermediates and final products, two new propargilic ethers and nine hybrid triazoles. In a second series, were synthesized substances 31, at where 4,7-dichloroquinoline was converted to 4-azide-7-chloroquinoline that, by "click" reactions with several terminal allkynes, afforded 25 new quinolinotriazoles. All the synthesized compounds have had their in vitro animalrial activity evaluated against W2 chloroquine resistant Plasmodium falciparum strain and cytotoxicity was assayed in HepG2 cell cultures. All the diterpene derivatives disclosed lower activity in comparison to the natural products, except the two propargilic ethers which showed IC50 19.7 ±3.8 and 83.4 ± 3.8 µM, as well two of the diterpene hybrids with IC50 53.0±5.1 e 56.3±8.1 µM. All of the quinolinotriazole hybrids were shown to be active against P. falciparum (W2). 14 out of these disclosed moderate activity with IC50 < 50 µM, in the range of 11.8 to 47.6 µM while 14 of these compounds were more active with IC50 between 1.72 and 8.66 µM. Moreover, all the quinolinotriazoles are of low cytotoxicity showing CC50 > 100 µM, some of them reaching CC50 >1000 µM. Therefore the quinolinotriazole hybrids might be considered of higher antimalarial potential than those derived from the kaurane diterpenes. On the other hand, on the basis of the kaurane propargilic ethers acivity here reported, these compounds might be regarded as new antimalarial hits and new kurane derivatives supporting hydrogen bonds donors are expected to be potential antimalarials as can be inferred from the molecular docking data.