Comparative Antimalarial Activities and ADME Profiles of Ozonides (1,2,4-trioxolanes) OZ277, OZ439, and Their 1,2-Dioxolane, 1,2,4-Trioxane, and 1,2,4,5-Tetraoxane Isosteres

Abstract

To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.

Crystal structure of 1-(adamantan-1-yl)-3-(3-chlorophenyl)thiourea, C17H21ClN2S

“…( )* malaria infections [11], central nervous disorders [12][13][14], hyperglycaemia [15] and drug-resistant TB strain infections [16]. As a part of our current research interest in the chemotherapeutic properties of adamantane derivatives [17][18][19] and the molecular structural of adamantyl thiourea analogues [20][21][22], we report herein the synthesis and crystal title structure.…”

Crystal structure of 1-(adamantan-1-yl)-3-(4-chlorophenyl)thiourea, C17H21ClN2S

“…In addition, numerous adamantanebased drugs are currently used as important medications against malaria [6], central nervous disorders [7][8][9], hyperglycaemia [10] and drug-resistant TB strain infections [11]. Moreover, thiourea derivatives were reported to possess marked anticancer [12], anti-HIV [13], antimalarial [14] and antimicrobial [15] activities.…”

Crystal structure of 1-(adamantan-1-yl)-3-(4-bromophenyl)thiourea, C17H21BrN2S

“…Moreover, several adamantanebased drugs are currently employed as important medications against malaria infections [7], central nervous disorders [8][9][10], hyperglycaemia [11] and drug-resistant TB strain infections [12]. In addition, thiourea derivatives were reported to display marked antitumor [13], anti-HIV [14], antimalarial [15] and antimicrobial [16] activities.…”