Abstract
The inhibition of the enzyme TMP kinase (TMPKmt), is hypothesized as a significant therapy for tuberculosis. A series of designed pyrimidines were synthesized to inhibit the enzyme TMPKmt and evaluated for their enzyme-ligand interactions, antitubercular, physiochemical and ADMET properties. The pyrimidines were synthesized from chalcones and guanidine as the cyclizing agent. The molecular interactions were studied by Autodock 4.0 and physicochemical, druglikeness and ADMET properties were analysed by Molinspiration, Chemsketch program and admetSAR prediction tools. The confirmation of the synthesized titled compound’s structures was by spectral analysis. Also, they were screened for their antitubercular activity. In silico studies reports that their physicochemical, ADMET and druglikeness properties were found to be in standard limit, which infers that, these compounds may not have problems with oral bioavailability. Molecular docking studies showed that the pyrimidines have better enzyme inhibitory activity onTMPKmt.
Highlights
Tuberculosis is one of the deadliest diseases, which are caused by the bacteria, Mycobacterium tuberculosis (Dye et al, 1998; Dye et al, 2002)
Owing to the growing resistance to today's leading anti tubercular drugs, new therapies are urgently needed, which stimulated the pursuit of novel targets for the disease tuberculosis
Chalcone and guanidine in equimolar quantities with anhydrous potassium carbonate as the catalyst resulted in pyrimidines in better yields (Table 1)
Summary
Tuberculosis is one of the deadliest diseases, which are caused by the bacteria, Mycobacterium tuberculosis (Dye et al, 1998; Dye et al, 2002). There are several flaws in existing drugs, the most prominent of which is the rise of drug resistance. For more than 20 years, no new medicines for tuberculosis have been discovered. Owing to the growing resistance to today's leading anti tubercular drugs, new therapies are urgently needed, which stimulated the pursuit of novel targets for the disease tuberculosis. The inactivation of suitable novel targets, which are responsible for bacterial metabolism, growth and viability, would lead to bacterial death, eliminating the drug-resistant strains and shortening the duration of the therapy (Zhang 2005; Mdluli et al, 2006)
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