title: Hybrids of thienopyrimidinones and thiouracils as anti-tubercular agents: SAR and docking studies.
abstract: 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.
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Mahesh M
authors.initials: MM
authors.lastname: Pisal
authors.affiliation: Combichem Bio-resource Centre, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Laxman U
authors.initials: LU
authors.lastname: Nawale
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Manoj D
authors.initials: MD
authors.lastname: Patil
authors.affiliation: Combichem Bio-resource Centre, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Sujit G
authors.initials: SG
authors.lastname: Bhansali
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Jayant M
authors.initials: JM
authors.lastname: Gajbhiye
authors.affiliation: Combichem Bio-resource Centre, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Subhash P
authors.initials: SP
authors.lastname: Chavan
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India. Electronic address: hb.borate@ncl.res.in.
authors.forename: Hanumant B
authors.initials: HB
authors.lastname: Borate
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010453:Peptide Synthases / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013889:Thiouracil / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000995:Antitubercular Agents; D011743:Pyrimidines; C476003:thienopyrimidine; D013889:Thiouracil; D010453:Peptide Synthases; C022318:pantothenate synthetase
keywords: Antitubercular activity; Docking; Thienopyrimidinone; Thiouracil; Tuberculosis