Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminate worms uses a 4–6 week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here we describe discovery and optimization of quinazolines CBR417 and CBR490 that with a single dose achieve > 99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, eight of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent anti-wolbachial activity was confirmed in L. sigmodontis, B. malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease, and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.