Hybrids of thienopyrimidinones and thiouracils as anti-tubercular agents: SAR and docking studies

• Published in: European journal of medicinal chemistry 2017-02, Vol.127, p.459-469
• Main Authors: Pisal, Mahesh M., Nawale, Laxman U., Patil, Manoj D., Bhansali, Sujit G., Gajbhiye, Jayant M., Sarkar, Dhiman, Chavan, Subhash P., Borate, Hanumant B.
• Format: Article
• Language: English
• Subjects: Antitubercular activity; Antitubercular Agents - chemistry; Antitubercular Agents - metabolism; Antitubercular Agents - pharmacology; Antitubercular Agents - toxicity; Catalytic Domain; Cell Line, Tumor; Docking; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis - drug effects; Peptide Synthases - chemistry; Peptide Synthases - metabolism; Pyrimidines - chemistry; Structure-Activity Relationship; Thienopyrimidinone; Thiouracil; Thiouracil - chemistry; Thiouracil - metabolism; Thiouracil - pharmacology; Thiouracil - toxicity; Tuberculosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.01.009

A number of hybrid molecules containing thienopyrimidinones and thiouracil moieties were designed, synthesized and tested against Mycobacterium tuberculosis H37Ra wherein it was observed that the compounds 11–14 exhibited antitubercular activity in vitro (MIC 7.6–19.1 μg/mL, 12–35 μM) against dormant stage while the compound 15 exhibited antitubercular activity in vitro against dormant (MIC 23.4 μg/mL, 41 μM) as well as active (MIC 25.4 μg/mL, 45 μM) stage. Structural modifications of the compound 15 were carried out to study the structure-activity relationship and it was observed that the compound 18 exhibited antitubercular activity comparable to the compound 15. Cytotoxicity studies revealed that these molecules were non-toxic. The docking study of the compound 15 showed that there was binding with the active site of mycobacterial pantothenate synthetase. Further docking studies led to the synthesis of the compounds 16 and 17 and the antitubercular activity screening results showed that these compounds have significant antitubercular activity. The compounds 15–18 (MIC 11–29 μg/mL, 19–51 μM) can be used as starting points for further optimization. The synthetic strategies used in the present work have potential to prepare a large number of compounds for further refinement of structures and the present results will be very useful in the development of a new class of antimycobacterial agents. [Display omitted] •New hybrids of thienopyrimidinones and thiouracils synthesized.•Some of the compounds exhibited significant antitubercular activity against MTB H37Ra.•The docking study done to predict the probable mode of action.•Inhibition of mycobacterial pantothenate synthetase predicted.