title: Development of selective DprE1 inhibitors: Design, synthesis, crystal structure and antitubercular activity of benzothiazolylpyrimidine-5-carboxamides.
abstract: Decaprenylphosphoryl-b-D-ribose 20-epimerase (DprE1) is a potential drug target for development of antitubercular agents. Structure based drug discovery approach yielded twenty novel derivatives of benzothiazolylpyrimidine-5-carboxamides (7a-t) which were synthesised by three component one pot reaction involving benzothiazolyl oxobutanamide, thiourea and substituted aromatic benzaldehydes. These derivatives were evaluated for antitubercular activity to determine MIC and compound 7a, 7e, 7f and 7o were found to be potentially active against Mycobacterium tuberculosis (H37Rv). Log P of these compounds was found to be between 2.0 and 3.0 making them suitable for oral dosing. DprE1 selectivity and pharmacokinetic studies were carried out for these compounds of which 7a and 7o were found to be highly selective and bioavailability was found to be above 52% by oral dose. Crystal structure of 7a was studied and molecular packing was determined, it exhibited a triclinic crystal lattice arrangement having hydrogen bonded dimeric arrangement. Drug receptor interactions were studied which exhibited docking in the active site of receptor with hydrogen bonding, hydrophobic interactions, vdW interactions with amino acid residues such as Cys387, Asn385, Lys418, Tyr314, Gln334 and Lys367 respectively. 3D QSAR analysis was carried out by kNN-MFA method to determine and develop theoretical model, best suitable model was found to be based on Simulated Annealing k-Neariest Neighbour Molecular Field Analysis (SA kNN-MFA). The model provided with hydrophobic descriptors in positive side indicating the need of bulky groups, steric and electronegative descriptors in negative coordinates hints with contribution by the electronegative substitutions as favourable and desirable moieties for enhancing the activity. The q(2), q(2)_se and Pred_r(2)se were found to be 0.5000, 0.6404 and 1.0094 respectively. A pharmacophore model was generated which suggested for necessity of aromatic, aliphatic carbon centre and hydrogen bond donor for development of newer DprE1 selective inhibitors.
authors: Computer Aided Drug Design Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440 033, MS, India. Electronic address: rupeshchikhale7@gmail.com.
authors: Rupesh
authors: R
authors: Chikhale
authors: Computer Aided Drug Design Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440 033, MS, India.
authors: Sunil
authors: S
authors: Menghani
authors: School of Chemistry, University of Hyderabad, C. R. Rao Road, Hyderabad 500 046, AP, India.
authors: Ramavath
authors: R
authors: Babu
authors: Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford BD7 1DP, West Yorkshire, United Kingdom.
authors: Ratnadeep
authors: R
authors: Bansode
authors: School of Chemistry, University of Hyderabad, C. R. Rao Road, Hyderabad 500 046, AP, India.
authors: G
authors: G
authors: Bhargavi
authors: Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford BD7 1DP, West Yorkshire, United Kingdom.
authors: Nazira
authors: N
authors: Karodia
authors: School of Chemistry, University of Hyderabad, C. R. Rao Road, Hyderabad 500 046, AP, India.
authors: M V
authors: MV
authors: Rajasekharan
authors: Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford BD7 1DP, West Yorkshire, United Kingdom.
authors: Anant
authors: A
authors: Paradkar
authors: Computer Aided Drug Design Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440 033, MS, India; Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford BD7 1DP, West Yorkshire, United Kingdom. Electronic address: pbkhedekarudps@gmail.com.
authors: Pramod
authors: P
authors: Khedekar
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D052160:Benzothiazoles; D011743:Pyrimidines; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis
keywords: 3D-QSAR; Benzothiazole; Crystal structure; DprE1 inhibitors; Molecular docking; Pharmacophore modelling