Synthesis, molecular modeling and biological evaluation of new pyrazolo[3,4-b]pyridine analogs as potential antimicrobial, antiquorum-sensing and anticancer agents.

TitleSynthesis, molecular modeling and biological evaluation of new pyrazolo[3,4-b]pyridine analogs as potential antimicrobial, antiquorum-sensing and anticancer agents.
Publication TypeJournal Article
Year of Publication2019
AuthorsEl-Gohary NS, Gabr MT, Shaaban MI
JournalBioorg Chem
Volume89
Pagination102976
Date Published2019 08
ISSN1090-2120
KeywordsAnti-Infective Agents, Antineoplastic Agents, Binding Sites, Cell Line, Tumor, Cell Survival, DNA, Drug Screening Assays, Antitumor, Fungi, Gram-Negative Bacteria, Gram-Positive Bacteria, Humans, Microbial Sensitivity Tests, Molecular Docking Simulation, Pyrazoles, Pyridines, Quorum Sensing, Structure-Activity Relationship
Abstract

New pyrazolo[3,4-b]pyridine analogs 2-9 were synthesized and subjected to antimicrobial testing toward chosen Gram-negative bacteria, Gram-positive bacteria and fungi. Compound 2 exhibited potent and extended-spectrum antimicrobial activity. Further, 6 and 9c demonstrated remarkable and extended-spectrum antibacterial activity. Antiquorum-sensing activity of the new members was tested over C. violaceum, whereas 9c demonstrated strong efficacy, while 2, 8b and 9b displayed moderate efficacy. In vitro anticancer assay toward HepG2, MCF-7 and Hela cancer cells manifested that 2 and 9c are powerful and extended-spectrum anticancer agents. Additionally, 8a, 8b and 9b showed excellent activity toward the three cancer cells. In vivo anticancer assay over EAC in mice indicated that 2 and 9c have the greatest activity. Moreover, cytotoxicity assay over WISH and W138 normal cells clarified that the checked analogs possess weak cytotoxicity toward the two normal cells. DNA-binding affinity was also tested, whereas 2, 3, 8b, 9b and 9c demonstrated great affinity. Molecular modeling studies revealed that the investigated compounds bind to DNA through intercalation similarly to doxorubicin. In silico studies revealed that the new members are anticipated to show excellent intestinal absorption.

DOI10.1016/j.bioorg.2019.102976
Alternate JournalBioorg Chem
PubMed ID31103494
Related Institute: 
Molecular Imaging Innovations Institute (MI3)

Weill Cornell Medicine
Department of Radiology
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