title: Unraveling the Alkaline Phosphatase Inhibition, Anticancer, and Antileishmanial Potential of Coumarin-Triazolothiadiazine Hybrids: Design, Synthesis, and Molecular Docking Analysis.
abstract: A series of new coumarin-triazolothiadiazine hybrid compounds (5a-j) was designed and synthesized by using the molecular hybridization concept. The cyclocondensation reaction involves the coumarinyl 4-amino-1,2,4-triazole and a range of bromo-acetophenones, delivering the desired products in good yields. The structures of the synthesized compounds were established on the basis of spectro-analytical data. The prepared compounds were evaluated against alkaline phosphatase (ALP) where compound 5j incorporating bis-coumarinyl motifs at the 3- and 6-positions of the heteroaromatic core turned out to be a potent inhibitor with an IC50 value of 1.15 ± 1.0 µM. The synthesized compounds were also tested against Leishmania major and 5h was the lead member with an IC50 value of 0.89 ± 0.08 μM. Anticancer activity was also determined using kidney fibroblast (BHK-21) and lung carcinoma (H-157) cancer cell lines. Compound 5i showed highest cytotoxic potential against H-157 cells with an IC50 value of 1.01 ± 0.12 μM, which is an improved inhibition compared to the standards (vincristine and cisplatin) used in this assay. Molecular docking studies were carried out on the synthesized library of coumarin-triazolothiadiazine hybrids against ALP. Almost all of the compounds showed strong interactions with the key residues of the active site of the receptor. In case of compounds 5a-c, 5h, and 5j, docking results positively complemented the experimental screening. These results provided substantial evidence for the further development of these compounds as potent inhibitors of ALP.
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Aliya
authors.initials: A
authors.lastname: Ibrar
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors.forename: Sumera
authors.initials: S
authors.lastname: Zaib
authors.affiliation: Department of Chemistry, Florida Center for Heterocyclic Compounds, University of Florida, Gainesville, FL, USA.|Center for Computationally Assisted Science and Technology, North Dakota State University, Fargo, ND, USA.
authors.forename: Farukh
authors.initials: F
authors.lastname: Jabeen
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Aamer
authors.initials: A
authors.lastname: Saeed
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D013829:Thiadiazines; D000469:Alkaline Phosphatase
keywords: Coumarin; Cytotoxicity; Heterocycles; Leishmaniasis; Triazolothiadiazine