Macrofilaricidal Benzimidazole–Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs

Abstract

A series of benzimidazole−benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.

Oxfendazole mediates macrofilaricidal efficacy against the filarial nematode Litomosoides sigmodontis in vivo and inhibits Onchocerca spec. motility in vitro

“…Thus, the L . sigmodontis rodent model was chosen by the Bill & Melinda Gates Foundation for the “Macrofilaricidal Drug Accelerator Program” to identify new compounds with a macrofilaricidal effect [ 17 , 23 – 25 , 54 , 55 ]. Despite this, all filarial rodent models have a shorter filarial life-span in comparison to human pathogenic filariae and differences in the location of the parasites and the associated accessibility of the drug to the filariae (thoracic cavity for L .…”

Onchocerciasis (river blindness) – more than a century of research and control

“…Taylor reported anti-filarial effects on Onchocerca microfilariae by perhexiline, a piperidine derivative affecting carnitine opalmitoyltransferase and the fatty acid oxidation pathway. Most recently, benzimidazole-benzoxborole hybrids, amide-or ketone-linked, termed 8a (AN8799) or 21 (AN15470), have been reported as promising macrofilaricidal agents tested to date in animal models (Akama et al, 2020).…”

Macrofilaricides: An Unmet Medical Need for Filarial Diseases

“…Anacor (currently Pfizer) reported several small molecule boron derived BZDs for the treatment of river blindness. Benzoxaborole-benzimidazole analogues of flubendazole were prepared to overcome the limited solubility and embryotoxicity associated with flubendazole. , Initially, 15 benzoxaborole compounds were exemplified in this class, demonstrating the killing of Brugia malayi adult worms in 1–2 days at 10 mM in vitro . Compounds J13 and J15 (Figure ) were exemplified, and J15 was one of the most potent compounds reported, killing 100% of the worms in 24 h when administered at 0.01 mM .…”

“…Compounds J13 and J15 (Figure ) were exemplified, and J15 was one of the most potent compounds reported, killing 100% of the worms in 24 h when administered at 0.01 mM . More recently, in the amide linked benzimidazole series, compound 8a showed acceptable pharmacokinetic properties, and when dosed subcutaneous as a suspension at 100 mg/kg/day for 14 days, demonstrated effective killing of B. malayi , B. pahangi , and L. sigmodontis worms in infected gerbils …”