title: Design, synthesis and pharmacological evaluation of pyrimidobenzothiazole-3-carboxylate derivatives as selective L-type calcium channel blockers.
abstract: L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50 on MLCK assay of 2.1±1.7 μM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40 μg/ml by oral route with Tmax reaching in 0.5 h which means in 30 min. 26 also exhibits superior t1/2 of 5.4 h and oral bioavailability of (F) 56.75% with an AUC0-∞ of 0.84 μg h/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be -3.602 and -47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series.
authors.affiliation: Computer Aided Drug Design Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440033, MS, India. Electronic address: rupeshchikhale7@gmail.com.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chikhale
authors.affiliation: Analytical Chemistry Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440033, MS, India.
authors.forename: Sonali
authors.initials: S
authors.lastname: Thorat
authors.affiliation: Computer Aided Drug Design Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440033, MS, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Pant
authors.affiliation: Centre for Bioinformatics, Pondicherry University, Pondicherry 605014, India.
authors.forename: Ankush
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: School of Chemistry, University of Hyderabad, C. R. Rao Road, Hyderabad 500 046, India.
authors.forename: Krishna Chary
authors.initials: KC
authors.lastname: Thatipamula
authors.affiliation: Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, West Yorkshire, United Kingdom.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Bansode
authors.affiliation: School of Chemistry, University of Hyderabad, C. R. Rao Road, Hyderabad 500 046, India.
authors.forename: G
authors.initials: G
authors.lastname: Bhargavi
authors.affiliation: Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, West Yorkshire, United Kingdom.
authors.forename: Nazira
authors.initials: N
authors.lastname: Karodia
authors.affiliation: School of Chemistry, University of Hyderabad, C. R. Rao Road, Hyderabad 500 046, India.
authors.forename: M V
authors.initials: MV
authors.lastname: Rajasekharan
authors.affiliation: Centre for Pharmaceutical Engineering Science, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, West Yorkshire, United Kingdom.
authors.forename: Anant
authors.initials: A
authors.lastname: Paradkar
authors.affiliation: Computer Aided Drug Design Laboratory, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur 440033, MS, India.
authors.forename: Pramod
authors.initials: P
authors.lastname: Khedekar
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011743:Pyrimidines; C000606946:ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido(2,1-b)(1,3)benzothiazole-3-carboxylate
keywords: 3D-QSAR; ACE; Benzothiazole; Hypertension; Myosin light chain kinase