Drug resistance hampers the treatment of giardiasis, one of the world’s most common gastro-intestinal parasitic diseases. On an annual basis an estimated 200 million people develop giardiasis, a disease that impacts child development and the general long-term health of many adults, particularly the disadvantaged. However, there is no vaccine for this disease and gold-standard treatment options are failing due to factors including variable activity and drug resistant parasites. Moreover, current treatment strategies are monotherapies that do little to prevent the development of drug resistant parasites. To improve this position combination therapies that include compounds with improved activity and unique mechanisms of action to currently used drugs are needed. However, little has been done to identify best practice combination therapies or to investigate combination strategies with new anti-Giardia agents. Our team has identified a new series of compounds with potent and selective activity against drug sensitive and resistant Giardia parasites.
Herein, we describe identification of thieno[3,2-b]pyrrole‑5‑carboxamide 1 as a hit (>90% inhibitory activity at 10 µM, over 48 h) [1], follow-up studies showing that 1 had promising activity (IC50 1.2 µM) and selectivity (NFF IC50 > 20 µM, selectivity index > 16), establishment of preliminary structure activity relationships by screening the Scaffold Library leading to identification of a more active analogue 2 which showed potent cytocidal activity (IC50 < 10 µM) against Giardia Assemblage B [2], and extensive synthesis and testing campaign to develop structure–activity relationships of the thienopyrrole series represented by 2 [3].