title: Synthesis, in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one schiff bases.
abstract: Development of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) has been considered as major health burden, globally. In order to develop novel, potential molecules against drug resistant TB, twenty two (22) new 3-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7-benzyl-2-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were designed and synthesized by using appropriate synthetic protocols. Pantothenate synthetase (PS) was considered as the target for the molecular docking studies and evaluated the binding pattern at active site, as PS plays a significant role in the biosynthesis of pantothenate in Mycobacterium tuberculosis (MTB). The preliminary in vitro antibacterial screening of test compounds was carried out against two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria. The antimycobacterial screening was performed against MTB H37Rv and an isoniazid-resistant clinical isolate of MTB. The compounds 6b, 6c, 6d, 6k, 7b, 7c, 7d and 7k exhibited promising antibacterial activity MIC in the range of 15-73 μM against all bacterial strains used and compounds 6d and 7b showed antimycobacterial activity (IC50 <340 μM in LRP assay) and (MIC <9 μM in broth microdilution method).
authors.affiliation: Medicinal Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India.
authors.forename: Malothu
authors.initials: M
authors.lastname: Narender
authors.affiliation: Medicinal Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India.
authors.forename: Bhandaru
authors.initials: B
authors.lastname: Jaswanth S
authors.affiliation: Medicinal Chemistry Division, Vaagdevi College of Pharmacy, Warangal, India.
authors.forename: Kulandaivelu
authors.initials: K
authors.lastname: Umasankar
authors.affiliation: Department of Microbiology, Sri Shivani College of Pharmacy, Warangal, India.
authors.forename: Jojula
authors.initials: J
authors.lastname: Malathi
authors.affiliation: Department of Microbiology, Sri Shivani College of Pharmacy, Warangal, India.
authors.forename: Adidala
authors.initials: A
authors.lastname: Raghuram Reddy
authors.affiliation: Bacteriology Division, National Institute for Research in Tuberculosis (NIRT), Chennai, India.
authors.forename: K R
authors.initials: KR
authors.lastname: Umadevi
authors.affiliation: Bacteriology Division, National Institute for Research in Tuberculosis (NIRT), Chennai, India.
authors.forename: A V N
authors.initials: AVN
authors.lastname: Dusthackeer
authors.affiliation: Pharmaceutical Chemistry Division, School of Pharmacy, International Medical University, Kualalumpur, Malaysia.
authors.forename: Kaki
authors.initials: K
authors.lastname: Venkat Rao
authors.affiliation: Medicinal Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India. Electronic address: raghumed@kakatiya.ac.in.
authors.forename: Akkinepally
authors.initials: A
authors.lastname: Raghuram R
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001665:Binding Sites; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D011743:Pyrimidines; D012545:Schiff Bases; C000601850:thieno(2,3-d)pyrimidine; D007538:Isoniazid
keywords: Antibacterial activity; LRP assay; MIC; Mycobacterium tuberculosis; Pyrido[4′,3′:4,5]thieno(2,3-d)pyrimidine-4-(3H)-one