Synthesis of novel-6.8-disubstituted-chromone-2-carboxylic acid derivatives and their biological evaluation as potential antimalarial agents

Abstract

Malaria is a mosquito vector-borne disease caused by a female anopheles mosquito belonging to a plasmodium genus, affecting more than 500 million people per annum. There are five plasmodium genus responsible for causing malaria, but four of them are responsible for causing human malaria. The most common one to cause malaria in Africa is P.Falciparum. The most commonly used drugs for malaria are quinine derivatives and artemisinin derivatives which are both derived from traditional plants. Malaria parasites have become resistance to almost all the currently used drugs. In this project different synthetic approaches were used to prepare novel chromone derivatives. This study was focused on the synthesis of various 6.8-substituted-chromone-2-carboxylic acids (41) derivatives from the corresponding 5-substituted-2-hydroxyacetophenones (38). The first step included the introduction of iodine on the 5-subsituted-2-hydroxyacetophenones (38) to give 5-substituted-3-iodo-2-hydroxyacetophenones (39A-D). The same step was repeated but with bromine to give 5-substituted-3-bromo-2-hydroxyacetophenones (39E-H). The 3.5-disubstituted-2-hydroxyacetophenones (39A-H) underwent condensation with diethyl oxalate and sodium ethoxide to form ethyl-6.8-disubstituted-chromone-2-carboxylates (40A-H), which was converted to the corresponding 6.8-disubstituted-carboxylic acids (41A-H). Attempted conversion of the acids to the corresponding carboxamides 43 via the carbonyl chloride intermediates (42A-D) was unsuccessful. The percentage yield of synthesized 3.5-disubstituted-hydroxyacetophenones (39A-H) ranged between 46-82 %, whilst those of ethyl-6.8-disubstituted-chromone-2-carboxylates (40A-H) intermediates ranged between 44-95 %. The yields of synthesized 6.8-disubstituted-chromone-2-carboxylic acids (41A-H) ranged between 48-98 % while the corresponding acids chlorides (42A-D) ranged between 44-60 %. Our attempted synthesis of 6.8-disubstituted-chromone-2-carboxamides (43) was unsuccessful. Compounds (39-43) were purified by recrystallization and characterized using NMR and FTIR spectroscopic techniques.