New series of fused pyrazolopyridines: Synthesis, molecular modeling, antimicrobial, antiquorum-sensing and antitumor activities.

New series of fused pyrazolopyridines were prepared and assessed for antimicrobial, antiquorum-sensing and antitumor activities. Antimicrobial evaluation toward selected Gram-positive bacteria, Gram-negative bacteria and fungi indicated that 5-phenylpyrazolopyridotriazinone 4a has good and broad-spectrum antimicrobial activity. In addition, 5-(4-chlorophenyl)pyrazolopyridotriazinone 4b and 5-(4-(dimethylamino)phenyl)pyrazolopyridotriazinone 4c exhibited good activity against the selected Gram-positive bacteria and A. fumigatus, whereas 5-amino-4-phenylpyrazolopyridopyrimidine 6a demonstrated good activity against B. cereus and P. aeruginosa. Furthermore, 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b demonstrated promising activity against the tested Gram-negative bacteria and fungi, and moderate activity against Gram-positive bacteria. Antiquorum-sensing screening over C. violaceum illustrated that 4a, 6a and 7a-c have strong activity. In vitro antiproliferative assessment of the new derivatives against HepG2, HCT-116 and MCF-7 cancer cells revealed that 7a is the most active analog against all tested cell lines. Likewise, 3,7-dimethyl-4-phenylpyrazolopyridopyrimidinone 2a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b manifested strong activity against all examined cell lines. In vivo antitumor testing of 2a, 7a and 7b against EAC cells in mice indicated that 7a has the highest activity. Cytotoxicity toward WI38 and WISH normal cells was also assessed and results assured that all of the investigated analogs have lower cytotoxicity than doxorubicin. DNA-binding affinity and topoisomerase IIß inhibitory activity were evaluated, and results revealed that 5b, 7a and 7b bind strongly to DNA; in addition, 2a, 4a, 7a and 7b manifested higher topoisomerase IIß inhibitory activity than that of doxorubicin. Analogs 5b, 7a and 7b were docked into topoisomerase IIß, and results indicated that 7a and 7b have the highest binding affinity toward topoisomerase IIß. In silico simulation studies referred that most of the new analogs comply with the optimum needs for good oral absorption. Also, computational carcinogenicity evaluation was predicted.

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

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.

Design, synthesis, antimicrobial, antiquorum-sensing and antitumor evaluation of new series of pyrazolopyridine derivatives.

New series of pyrazolopyridines 1-15 were synthesized and esteemed for antimicrobial effectiveness against S. aureus, B. cereus, E. coli, P. aeruginosa, C. albicans, A. fumigatus and A. flavus. Analogs 15c and 15d have eminent and broad spectrum antimicrobial activity, while 13a, 15a, 15e and 15f have potent effectiveness on S. aureus and B. cereus. In addition, 12 exhibited excellent effectiveness on E. coli and P. aeruginosa. Compounds 1-15 were also evaluated for antiquorum-sensing efficacy over C. violacium, whereas 11a, 15b, 15e and 15f showed reasonable efficacy. In vitro antitumor testing of the new analogs against HepG2, MCF-7 and Hela cancer cell lines revealed that 1 and 15d have potent and broad spectrum antitumor activity. In addition, 4, 8 and 15f showed prominent effectiveness on the three chosen cancer cell lines. In vivo antitumor assessment toward EAC in mice revealed that compounds 1 and 15d have the highest efficacy. Furthermore, cytotoxicity evaluation against W138 and WISH normal cells indicated that all screened compounds have lower cytotoxicity than doxorubicin over both normal cell lines. The active antimicrobial and antitumor compounds were estimated for DNA-binding affinity. Compounds 1, 15c and 15d exhibited strong affinity, and they were subsequently docked into DNA, where they displayed good interactions with DNA. In silico studies indicated that the new compounds are predicted to exhibit good oral absorption.

New pyrazolopyridine analogs: Synthesis, antimicrobial, antiquorum-sensing and antitumor screening.

New pyrazolopyridine analogs were prepared and tested for antimicrobial efficacy toward Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Aspergillus fumigatus and Aspergillus flavus. Results revealed that compound 6 has prominent and broad spectrum antimicrobial activity. Compound 8 showed good antibacterial efficacy over the four tested bacterial strains. In addition, compounds 2-4 displayed interesting efficacy over S. aureus, B. cereus and P. aeruginosa as well as moderate efficacy toward E. coli, C. albicans, A. fumigatus and A. flavus. Furthermore, compounds 9 and 10 exhibited interesting efficacy over P. aeruginosa. Antiquorum-sensing efficacy of the same analogs toward Chromobacterium violaceum was also examined, whereas compounds 3, 4 and 6 displayed acceptable activity. In vitro antitumor assay of the new pyrazolopyridines toward liver (HepG2), breast (MCF-7) and cervix (Hela) cancer cells illustrated that compounds 2 and 5 have the highest antitumor activity over the three cell lines. Moreover, compound 4 exhibited interesting efficacy on all tested cell lines, whereas compound 7 showed good activity on MCF-7 cells. The most active in vitro antitumor analogs, 2, 4, 5 and 7 were assessed for in vivo antitumor efficacy on Ehrlich ascites carcinoma (EAC) cells, whereas compound 5 displayed the highest efficacy. In addition, cytotoxicity testing toward W138 and WISH normal cells revealed that all tested analogs are less cytotoxic than doxorubicin. The new analogs were evaluated for DNA-binding affinity, whereas compounds 2, 4 and 5 displayed the highest affinity. In silico studies concluded that all the new pyrazolopyridines are foreseen to have excellent oral absorption.

Synthesis, antimicrobial, antiquorum-sensing and antitumor activities of new benzimidazole analogs.

New benzimidazole analogs were prepared and tested for antimicrobial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85, Staphylococcus aureus ATCC 29213, Candida albicans and Aspergillus fumigatus 293. Results indicated that compound 10 has potent and broad spectrum antimicrobial activity. In addition, 4b and 5c showed eminent antimicrobial efficacy toward B. cereus, S. aureus, C. albicans and A. fumigatus. Furthermore, 12 and 14 demonstrated interesting antifungal activity toward C. albicans. Antiquorum-sensing efficacy of the new compounds toward Chromobacterium violacium ATCC 12472 was also examined. In vitro antitumor screening of the new benzimidazoles toward HepG2, HCT-116 and MCF-7 cancer cell lines demonstrated that 4b and 5b,c are the most potent analogs toward all tested cell lines. The three potent in vitro antitumor analogs were further assessed for in vivo antitumor activity toward EAC in mice, and in vitro cytotoxicity toward W138 normal cell line. Results revealed that 4b has the highest in vivo activity, and that the three tested analogs are less cytotoxic than 5-FU toward W138 normal cell line. The most active antimicrobial and antitumor analogs were examined for DNA-binding affinity, whereas 4b and 5c displayed the highest affinity. The in silico studies illustrated that all of the new benzimidazoles meet the optimal requirements for good oral absorption and bioavailability. Moreover, in silico toxicity assessment has been reported.

Synthesis and biological evaluation of a new series of benzimidazole derivatives as antimicrobial, antiquorum-sensing and antitumor agents.

New benzimidazole derivatives were synthesized and assessed for antimicrobial efficacy toward Escherichia coli, Bacillus cereus, Staphylococcus aureus, Candida albicans and Aspergillus fumigatus 293. Results indicated that compounds 3c and 3n have promising activity toward S. aureus, whereas 3i exhibited remarkable efficacy toward B. cereus. Moreover, compound 3c was proved to be the most active antifungal analog toward C. albicans. On the other hand, 3n displayed the highest activity against A. fumigatus 293. Antiquorum-sensing activity of the same compounds was also tested against Chromobacterium violacium ATCC 12472, whereas compounds 3c-f, 3i-k and 3m-o showed acceptable activity. In vitro antitumor testing of these compounds toward liver cancer (HepG2), colon cancer (HCT-116) and breast cancer (MCF-7) cell lines revealed that compound 3p has the highest potency against the three tested cell lines. Moreover, 3f, 3m and 3n displayed promising activity toward all tested cell lines. Compounds 3f, 3m, 3n and 3p were esteemed for in vivo antitumor activity against EAC cells. The active antimicrobial and antitumor analogs, 3a, 3c, 3f, 3i-k, 3m, 3n and 3p were assessed for DNA-binding affinity, and results indicated that 3c, 3f, 3i, 3k and 3n have strong DNA-binding affinity. The computational studies affirmed that almost all of the inspected compounds meet the optimal requirements for good absorption and oral bioavailability.

Sodium ascorbate as a quorum sensing inhibitor of Pseudomonas aeruginosa.

AIMS: Quorum sensing circuits regulate virulence factors in Pseudomonas aeruginosa and coordinate bacterial pathogenicity. We are interested in exploring available medications for their antiquorum sensing activity. METHODS AND RESULTS: First, we determined the MIC of ascorbate against Ps. aeruginosa strain PAO1, and all further experiments used concentrations below the MIC so that results could not be caused by reduced viability. Tests of subinhibitory concentrations of sodium ascorbate on cell signals were performed using a reporter strain assay. Sub-MICs of sodium ascorbate resulted in significant reduction of the signalling molecules C4-HSL and 3-oxo-C12-HSL (P < 0·01). The influence of sub-MIC of sodium ascorbate on virulence factors was also determined and ascorbate treatment led to significant depression of elastase, protease and haemolysin activities. In addition, inhibition of pyocyanin production, attenuation of biofilm formation and alteration of Pseudomonas motility was observed. Analysis by RT-PCR tested the effect of ascorbate on the expression of QS regulatory genes. Expression of QS regulatory genes, lasI, lasR, rhlI, rhlR, pqsR and pqsA, was repressed compared to untreated Ps. aeruginosa PAO1, confirming that ascorbate QS inhibition works on gene expression at the molecular level. CONCLUSION: Sodium ascorbate, even at low concentrations, inhibited QS and related virulence factors of Ps. aeruginosa PAO1. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated that sodium ascorbate could function as signal modulator and virulence inhibitor in Ps. aeruginosa.