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 synthesized
47 analogues, which allowed us to define features of the molecules
essential for anthelmintic action as well as broadening the chemotype
by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic
activity. We investigated the activity of these compounds against
other parasitic nematodes, identifying DHB compounds with activity
against
Brugia malayi
and
Heligmosomoides
polygyrus
. We also demonstrated activity of DHB compounds
against the trematode
Schistosoma mansoni,
a parasite
that causes schistosomiasis. These results demonstrate the potential
of DHB and DBQ compounds for further development as broad-spectrum
anthelmintics.