Exploring Acyl Thiotriazinoindole Based Pharmacophores: Design, Synthesis, and SAR Studies with Molecular Docking and Biological Activity Profiling against Urease, α-amylase, α-glucosidase, Antimicrobial, and Antioxidant Targets.

Publisher: Springer Country of Publication: Netherlands NLM ID: 101212092 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1875-8355 (Electronic) Linking ISSN: 15723887 NLM ISO Abbreviation: Protein J Subsets: MEDLINE

Publication: 2005- : Dordrecht : Springer
Original Publication: Dordrecht, The Netherlands ; New York : Kluwer Academic/Plenum, c2004-

alpha-Amylases*/antagonists & inhibitors ; alpha-Amylases*/chemistry ; alpha-Glucosidases*/chemistry ; alpha-Glucosidases*/metabolism ; Antioxidants*/chemistry ; Antioxidants*/pharmacology ; Antioxidants*/chemical synthesis ; Urease*/antagonists & inhibitors ; Urease*/chemistry; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/chemical synthesis ; Drug Design ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemical synthesis ; Glycoside Hydrolase Inhibitors/chemistry ; Glycoside Hydrolase Inhibitors/pharmacology ; Glycoside Hydrolase Inhibitors/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacology ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Structure-Activity Relationship

A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5 h with para cyano group manifested the most pivotal biological activity among all, displaying IC 50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9 µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5 g possessing a p-CH 3 at phenyl ring unfolded as most active, with calculated IC 50 values 90.3 ± 1.1 µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC 50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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Keywords: Acyl thiotriazinoindoles; Antibacterial; Antifungal; Enzyme inhibition; Heterocycles; Molecular docking

EC 3.2.1.1 (alpha-Amylases)
EC 3.2.1.20 (alpha-Glucosidases)
0 (Anti-Bacterial Agents)
0 (Antioxidants)
0 (Enzyme Inhibitors)
0 (Glycoside Hydrolase Inhibitors)
0 (Indoles)
EC 3.5.1.5 (Urease)

Date Created: 20240902 Date Completed: 20240928 Latest Revision: 20241004

20241004

10.1007/s10930-024-10229-6

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