Synthetic studies of novel chromone-2- carboxylate derivatives and their biological evaluations

Abstract

Chromones are a group of naturally occurring heterocyclic compounds, with oxygen as a heteroatom. However, chromone-2-carboxylates are scarce in nature. These compounds are significant in organic chemistry and medicinal chemistry due to their wide range of biological activities which include anti-HIV, anti-tuberculosis, anti-malaria, etc. The present study focus on the synthesis of chromone-2-carboxylate derivatives and their biological evaluations. Three pathways were followed to synthesize different target compounds. In the first pathway, chromone-2-carboxylates (51A-F) were successfully synthesized from 2-hydroxyacetophenones, followed by the treatment with the hydrazine, to form chromone-2-carbohydrazide derivatives (52A-F). Subsequently, the carbohydrazide cyclised to form 2-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl) chromone derivatives (53A-E). The second pathway started with the brominating of 2-hydroxyacetophenones at position 3, there-after it followed the same pathway as the first pathways to 2-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl) chromone derivatives (57A-C). The third route involved the ring opening of the chromone-2-carboxylate, to achieve ethyl 4-(3-bromo-5-chloro-2-hydroxyphenyl)-2-morpholino-4-oxobut-2-enoate 58. The ethoxy moiety of ethyl 4-(3-bromo-5-chloro-2-hydroxyphenyl)-2-morpholino-4-oxobut-2-enoate 58 was substituted with the hydrazine moiety to form 6-(3-bromo-5-chloro-2-hydroxyphenyl)-4-morpholinopyridazin-3(2H)-one 59. Compounds were characterized by 1D & 2D NMR, IR spectroscopy, HRMS, elemental analysis (CHN analysis) and the physical data of the compounds. 15 compounds were tested for biological activity against malaria. These synthesized chromone-2-carboxylate derivatives samples were tested in triplicate on two occasions over 72 hours against both the wild-type drug-sensitive strain of the human malaria parasite Plasmodium falciparum NF54 and a multidrug-resistant strain Plasmodium falciparum K1. Amongst all tested compounds, 51D, 55B, 52A, 52C and 59 displayed activities against chloroquine sensitive (NF54) stains of Plasmodium falciparum, with 78.33 %, 88.66 %, 72.16 %, 69.5 %, and 0.195 % viability respectively which were all below the positive control. Compounds 51E, 55D, and 59 displayed activities against chloroquine resistant (K1) strains of Plasmodium falciparum, with 57.5 %, 84.33 %, and 19,5 % viability respectively which were also below that of the positive control.