title: Design, synthesis and evaluation of small molecule imidazo[2,1-b][1,3,4]thiadiazoles as inhibitors of transforming growth factor-β type-I receptor kinase (ALK5).
abstract: A new series of imidazo[2,1-b][1,3,4]thiadiazoles 5(a-g), 6(a-g), 9(a-i) and 12(a-h) were synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d, 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC50 = 0.0012 μM) and elective inhibition (91%) against the P38αkinase at10 μM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors.forename: Harun M
authors.initials: HM
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Chemistry, ASBASJSM College of Pharmacy, Bela (Ropar) 140111, Punjab, India.
authors.forename: Baljeet
authors.initials: B
authors.lastname: Sing
authors.affiliation: Department of Biotechnology, Bioinformatics and Pharmacy, Jaypee University of Information Technology, Waknaghat, Solan 173234, Himachal Pradesh, India.
authors.forename: Varun
authors.initials: V
authors.lastname: Bhardwaj
authors.affiliation: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Palkar
authors.affiliation: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors.forename: Mahamadhanif S
authors.initials: MS
authors.lastname: Shaikh
authors.affiliation: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rane
authors.affiliation: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa.
authors.forename: Wesam S
authors.initials: WS
authors.lastname: Alwan
authors.affiliation: School Pharmacy, Faculty of Medical Sciences, EWMS Complex, Mt. Hope, The University of the West Indies, Trinidad and Tobago, West Indies.
authors.forename: Andanappa K
authors.initials: AK
authors.lastname: Gadad
authors.affiliation: Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim (Surat) 3941110, Gujarat, India. Electronic address: mallesh7301@rediffmail.com.
authors.forename: Malleshappa N
authors.initials: MN
authors.lastname: Noolvi
authors.affiliation: Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Private Bag X54001, Durban 4000, South Africa. Electronic address: karpoormath@ukzn.ac.za.
authors.forename: Rajshekhar
authors.initials: R
authors.lastname: Karpoormath
mesh_terms: D018938:Caco-2 Cells; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D013830:Thiadiazoles; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
keywords: ALK5; Lipinski's rule; Synthesis imidazo [2,1-b][1,3,4]thiadiazole; XP docking