Urea Derivatives of 2‑Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis

A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. <b>2016</b>, 24, 2451–2465) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)­ethyl-4-phenylthiazole (<b>1</b>), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (<i>S</i>)-2-(3,4-difluorophenyl)-5-(3-fluoro-<i>N</i>-pyrrolidylamido)­benzothiazole (<b>57</b>) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease

Urea Derivatives of 2‑Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis

A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. <b>2016</b>, 24, 2451–2465) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)­ethyl-4-phenylthiazole (<b>1</b>), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (<i>S</i>)-2-(3,4-difluorophenyl)-5-(3-fluoro-<i>N</i>-pyrrolidylamido)­benzothiazole (<b>57</b>) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease

Substituted 2-phenylimidazopyridines : a new class of drug leads for human African trypanosomiasis

A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl)oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of 64, a substituted 2-(3-aminophenyl)imidazopyridine. This compound showed antiparasitic activity in vitro with an EC50 of 2 nM and displayed reasonable druglike properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound 64 cured mice infected with Trypanosoma brucei when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound 64 represents a new lead for the development of drugs to treat human African trypanosomiasis

Substituted 2‑Phenylimidazopyridines: A New Class of Drug Leads for Human African Trypanosomiasis

A phenotypic screen of a compound library for antiparasitic activity on <i>Trypanosoma brucei</i>, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl)­oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of <b>64</b>, a substituted 2-(3-aminophenyl)­imidazopyridine. This compound showed antiparasitic activity in vitro with an EC₅₀ of 2 nM and displayed reasonable druglike properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound <b>64</b> cured mice infected with <i>Trypanosoma brucei</i> when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound <b>64</b> represents a new lead for the development of drugs to treat human African trypanosomiasis