Delving into the Latest Updates on TMPK inhibitors(Ghent University) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

alpha-Thymidine derivative 15(Ghent University)

Target

DTYMK

Mechanism

DTYMK inhibitors(deoxythymidylate kinase inhibitors)

Therapeutic Areas

Infectious DiseasesOther Diseases

Active Indication

Mycobacterium Tuberculosis, Susceptibility to Infection By

Inactive Indication-

Originator Organization

Ghent University

Active Organization

Ghent University

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC18H18ClF3N4O4S

InChIKeyIJDGQXGQAWBJEG-MJBXVCDLSA-N

CAS Registry954117-16-9

New Biginelli adducts were rationalised, via the introduction of selected anti-tubercular (TB) pharmacophores into the dihydropyrimidine (DHPM) ring of deoxythymidine monophosphate (dTMP), the natural substrate of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt). Repurposing was one of the design rationale strategies for some selected mimics of the designed compounds. The anti-TB activity was screened against the Mtb H₃₇Rv strain where 11a was superior to ethambutol (EMB), and was 9-fold more potent than pyrazinamide (PZA). Additionally, compounds 11b, 4a, 4b, 13a, 13b and 14a elicited higher anti-TB activity than PZA, showing better safety profiles than EMB against RAW 264.7 cells' growth. The in vitro TMPKmt inhibition assay released compounds 11a, 11b and 13b as the most potent inhibitors. Docking studies presumed the binding modes and molecular dynamics (MD) simulation revealed the dynamic stability of 11a-TMPKmt complex over 100 ns. In silico prediction of the chemo-informatics properties of the most active compounds was conducted.

100 Deals associated with TMPK inhibitors(Ghent University)

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