US 12,396,969 B2 · Compounds and methods for the treatment of parasitic infections

Abstract

Cryptosporidium parvum is a highly prevalent zoonotic and anthroponotic protozoan parasite that causes a diarrheal syndrome in children and neonatal livestock, culminating in growth retardation and mortalities. Disclosed herein are inhibitors against the enzymatic activity of recombinant CpLDH protein that were identified. The inhibitors were tested for anti-Cryptosporidium effect using in vitro infection assays of HCT-8 cells monolayers. Compounds NSC158011 and NSC10447 were identified to inhibit the proliferation of intracellular C. parvum in vitro, with IC50 values of 14.88 and 72.65 μM, respectively. At doses tolerable in mice, both NSC158011 and NSC10447 significantly reduced the shedding of C. parvum oocysts in infected immunocompromised mice's feces and prevented intestinal villous atrophy as well as mucosal erosion due to C. parvum. These findings have unveiled anti-Cryptosporidium drug candidates that can be explored further for the development of therapeutic agents against C. parvum infections.

Claims19

Dependent claims

A method for treating a parasitic infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or Formula II:

or a salt thereof;
wherein
J1 and J3 are each independently S, O, or NRZ wherein RZ is H, —(C1-C6)alkyl, or (C3-C6) cycloalkyl;
J2 is NRZ, S, O;
X1 and X2 are independently O or S;
R1 is aryl,
heterocycloalkyl, or heteroaryl;
R2 is H, halo, OH, SH, NRARB, —C(═O)ORC, —S(═O)2NRCRD, —(C1-C6)alkyl, —O(C1-C6)alkyl, —S(C1-C6)alkyl, —(C3-C6) cycloalkyl, —O(C3-C6) cycloalkyl, —S(C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein aryl or heteroaryl is unsubstituted or substituted;
R3 is H, halo, or OH;
R4 and R5 are independently halo, OH, SH, NRARB, —C(═O)ORC, or —S(═O)2NRCRD;
R6 is H, —(C1-C6)alkyl, or —(C3-C6) cycloalkyl;
R7, R8 and R9 are independently OH, halo, SH, NRARB, —C(═O)ORC, or —S(═O)2NRCRD;
R10 and R11 are independently halo, OH, SH, NRARB, —C(═O)ORC, —S(═O)2NRCRD;
and
RA, RB, RC, and RD are each independently H, —(C1-C6)alkyl, or —(C3-C6) cycloalkyl;
thereby killing or inhibiting the growth of parasites in the subject;
wherein the parasite of the parasitic infection is Cryptosporidium parvum.

14 more elements

Dependencies are inferred from the claim text.

Compounds and methods for the treatment of parasitic infections

Life of this patent

Compounds and methods for the treatment of parasitic infections

Life of this patent

Abstract

Claims19