TY - JOUR
T1 - Activity of (1-benzyl-4-triazolyl)-indole-2-carboxamides against Toxoplasma gondii and Cryptosporidium parvum
AU - Khan, Shahbaz M.
AU - Garcia Hernandez, Anolan
AU - Allaie, Idrees Mehraj
AU - Grooms, Gregory M.
AU - Li, Kun
AU - Witola, William H.
AU - Stec, Jozef
N1 - Publisher Copyright:
© 2022
PY - 2022/8
Y1 - 2022/8
N2 - Parasitic diseases such as toxoplasmosis and cryptosporidiosis remain serious global health challenges, not only to humans but also to domestic animals and wildlife. With only limited treatment options available, Toxoplasma gondii and Cryptosporidium parvum (the causative agents of toxoplasmosis and cryptosporidiosis, respectively) constitute a substantial health threat especially to young children and immunocompromised individuals. Herein, we report the synthesis and biological evaluation of a series of novel (1-benzyl-4-triazolyl)-indole-2-carboxamides and related compounds that show efficacy against T. gondii and C. parvum. Closely related analogs 7c (JS-2-30) and 7e (JS-2-44) showed low micromolar activity with IC50 indices ranging between 2.95 μM and 7.63 μM against both T. gondii and C. parvum, whereas the compound representing (1-adamantyl)-4-phenyl-triazole, 11b (JS-2-41), showed very good activity with an IC50 of 1.94 μM, and good selectivity against T. gondii in vitro. Importantly, compounds JS-2-41 and JS-2-44 showed appreciable in vivo efficacy in decreasing the number of T. gondii cysts in the brains of Brown Norway rats. Together, these results indicate that (1-benzyl-4-triazolyl)-indole-2-carboxamides and (1-adamantyl)-4-phenyl-triazoles are potential hits for medicinal chemistry explorations in search for novel antiparasitic agents for effective treatment of cryptosporidiosis and toxoplasmosis.
AB - Parasitic diseases such as toxoplasmosis and cryptosporidiosis remain serious global health challenges, not only to humans but also to domestic animals and wildlife. With only limited treatment options available, Toxoplasma gondii and Cryptosporidium parvum (the causative agents of toxoplasmosis and cryptosporidiosis, respectively) constitute a substantial health threat especially to young children and immunocompromised individuals. Herein, we report the synthesis and biological evaluation of a series of novel (1-benzyl-4-triazolyl)-indole-2-carboxamides and related compounds that show efficacy against T. gondii and C. parvum. Closely related analogs 7c (JS-2-30) and 7e (JS-2-44) showed low micromolar activity with IC50 indices ranging between 2.95 μM and 7.63 μM against both T. gondii and C. parvum, whereas the compound representing (1-adamantyl)-4-phenyl-triazole, 11b (JS-2-41), showed very good activity with an IC50 of 1.94 μM, and good selectivity against T. gondii in vitro. Importantly, compounds JS-2-41 and JS-2-44 showed appreciable in vivo efficacy in decreasing the number of T. gondii cysts in the brains of Brown Norway rats. Together, these results indicate that (1-benzyl-4-triazolyl)-indole-2-carboxamides and (1-adamantyl)-4-phenyl-triazoles are potential hits for medicinal chemistry explorations in search for novel antiparasitic agents for effective treatment of cryptosporidiosis and toxoplasmosis.
KW - (1-Benzyl-4-triazolyl)-indole-2-carboxamides
KW - (1-adamantyl)-4-phenyl-triazoles
KW - Antiprotozoal agents
KW - Cryptosporidium parvum
KW - Drug discovery
KW - Toxoplasma gondii
UR - http://www.scopus.com/inward/record.url?scp=85128665339&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128665339&partnerID=8YFLogxK
U2 - 10.1016/j.ijpddr.2022.04.001
DO - 10.1016/j.ijpddr.2022.04.001
M3 - Article
C2 - 35462232
AN - SCOPUS:85128665339
SN - 2211-3207
VL - 19
SP - 6
EP - 20
JO - International Journal for Parasitology: Drugs and Drug Resistance
JF - International Journal for Parasitology: Drugs and Drug Resistance
ER -