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Synthesis, molecular modeling and biological evaluation of new pyrazolo[3,4-b]pyridine analogs as potential antimicrobial, antiquorum-sensing and anticancer agents. 2019

N S El-Gohary, and M T Gabr, and M I Shaaban
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: dr.nadiaelgohary@yahoo.com.

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.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D011720 Pyrazoles Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004354 Drug Screening Assays, Antitumor Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals. Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D005658 Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including MUSHROOMS; YEASTS; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Fungi, Filamentous,Molds,Filamentous Fungi,Filamentous Fungus,Fungus,Fungus, Filamentous,Mold
D006090 Gram-Negative Bacteria Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method. Gram Negative Bacteria
D006094 Gram-Positive Bacteria Bacteria which retain the crystal violet stain when treated by Gram's method. Gram Positive Bacteria
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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