Presentation Type
Paper
Abstract
Malaria exceeds 200 million annual cases worldwide due to increasing parasitic resistance to commonly available antimalarial drugs such as atovaquone. The objective of this research is to prepare 1,2,3,4-tetrahydroacridin-9(10H)-one(THA) derivatives (by utilizing structure-activity relationship (SAR) studies of the benzenoid ring of the THA scaffold) to test for activity against P. falciparum isolates TM90-C2B (an atovaquone-resistant strain) and W2 (an atovaquone-susceptible strain). Synthesis of THAs involves refluxing substituted anthranilic acids in phosphorus oxychloride (POCl3) with cycloalkanones to form various 9-chloro-1,2,3,4-tetrahydroacridines. Subsequent hydrolysis in acetic acid yields the respective THA. When compounds were screened in vitro against blood stages of P. falciparum, results indicated that Me–,Cl–, and MeO– substituted THAs reduced parasite activity better than F– and NO2– substituents. Based on the SAR studies, a disubstituted THA (7-chloro-6-methoxy-THA) was predicted to best inhibit parasitic activities. Ultimately, the 7-chloro-6-methoxy-THA delivered the best results, most likely attributed by a synergistic effect in structural activity. In fact, monosubstituted 6-methoxy-THA and 7-chloro-THA effectively reduced parasite activity by 12-14 fold when compared against a standard unsubstituted THA. Herein, this research examines the effects of different substituents on parasitic activity, which can be used to further enhance or develop other similar drug candidates.
Authors: Lisa Luong, R. Matthew Cross1, Justin Sargent1, Jordany Maignan1, Tina Mutka2, Dennis E. Kyle2, Roman Manetsch*,1
1 University of South Florida, Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, CMD5, College of Arts and Sciences Tampa, FL, United States.
2 University of South Florida, Global Health, College of Public Health, Tampa, FL, United States.
Categories
Natural Sciences
Research Type
Thesis
Mentor Information
Dr. Roman Manetsch
Included in
Development of 1,2,3,4-Tetrahydroacridin-9(10H)-ones as Potential Inhibitors of P.falciparum isolates TM90-C2B & W2 via Structure Activity Relationship (SAR) Studies
Malaria exceeds 200 million annual cases worldwide due to increasing parasitic resistance to commonly available antimalarial drugs such as atovaquone. The objective of this research is to prepare 1,2,3,4-tetrahydroacridin-9(10H)-one(THA) derivatives (by utilizing structure-activity relationship (SAR) studies of the benzenoid ring of the THA scaffold) to test for activity against P. falciparum isolates TM90-C2B (an atovaquone-resistant strain) and W2 (an atovaquone-susceptible strain). Synthesis of THAs involves refluxing substituted anthranilic acids in phosphorus oxychloride (POCl3) with cycloalkanones to form various 9-chloro-1,2,3,4-tetrahydroacridines. Subsequent hydrolysis in acetic acid yields the respective THA. When compounds were screened in vitro against blood stages of P. falciparum, results indicated that Me–,Cl–, and MeO– substituted THAs reduced parasite activity better than F– and NO2– substituents. Based on the SAR studies, a disubstituted THA (7-chloro-6-methoxy-THA) was predicted to best inhibit parasitic activities. Ultimately, the 7-chloro-6-methoxy-THA delivered the best results, most likely attributed by a synergistic effect in structural activity. In fact, monosubstituted 6-methoxy-THA and 7-chloro-THA effectively reduced parasite activity by 12-14 fold when compared against a standard unsubstituted THA. Herein, this research examines the effects of different substituents on parasitic activity, which can be used to further enhance or develop other similar drug candidates.
Authors: Lisa Luong, R. Matthew Cross1, Justin Sargent1, Jordany Maignan1, Tina Mutka2, Dennis E. Kyle2, Roman Manetsch*,1
1 University of South Florida, Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, CMD5, College of Arts and Sciences Tampa, FL, United States.
2 University of South Florida, Global Health, College of Public Health, Tampa, FL, United States.
