Abstract
Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However low single dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define essential features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We also investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.
Competing Interest Statement
The authors have declared no competing interest.
