WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 555200
Description: VCC234718 is a IMPDH inhibitor.VCC234718 showed growth inhibitory activity against Mycobacterium tuberculosis (Mtb). VCC234718 was identified by phenotypic screening of a 15344-compound library. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD+. VCC234718 inhibits Mtb GuaB2 with a Ki of 100 nM and is uncompetitive with respect to IMP and NAD+.
MedKoo Cat#: 555200
Chemical Formula: C20H25N3O3S
Exact Mass: 387.1617
Molecular Weight: 387.498
Elemental Analysis: C, 61.99; H, 6.50; N, 10.84; O, 12.39; S, 8.27
Synonym: VCC234718; VCC-234718; VCC 234718.
IUPAC/Chemical Name: Cyclohexyl[4-(5-isoquinolinylsulfonyl)-1-piperazinyl]methanone
InChi Key: RQGSIJUNMAAIRB-UHFFFAOYSA-N
InChi Code: InChI=1S/C20H25N3O3S/c24-20(16-5-2-1-3-6-16)22-11-13-23(14-12-22)27(25,26)19-8-4-7-17-15-21-10-9-18(17)19/h4,7-10,15-16H,1-3,5-6,11-14H2
SMILES Code: O=C(C1CCCCC1)N2CCN(S(=O)(C3=CC=CC4=C3C=CN=C4)=O)CC2
This compound binds at the NAD+ site, after IMP has bound, and makes direct interactions with IMP; therefore, the inhibitor is by definition uncompetitive. VCC234718 forms strong pi interactions with the Y487 residue side chain from the adjacent protomer in the tetramer, explaining the resistance-conferring mutation. In addition to sensitizing Mtb to VCC234718, depletion of GuaB2 was bactericidal in Mtb in vitro and in macrophages. When supplied at a high concentration (≥125 μM), guanine alleviated the toxicity of VCC234718 treatment or GuaB2 depletion via purine salvage. However, transcriptional silencing of guaB2 prevented Mtb from establishing an infection in mice, confirming that Mtb has limited access to guanine in this animal model. Together, these data provide compelling validation of GuaB2 as a new tuberculosis drug target.
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