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.

Nebulizer therapy with antibiotics in chronic suppurative lung disease.

Aerosolized antibiotics have been shown to be a useful modality of treatment in patients with cystic fibrosis. In this investigation we examined the utility of this treatment in patients with other chronic suppurative lung disorders. These included forty patients, thirty men and ten women with chronic airway infection (27 with bronchiectasis, 6 with chronic abscess and 7 with chronic suppurative bronchitis). Pathogenic organisms were isolated from the affected part of the lung by a fiberoptic bronchoscopy using a sterile disposable bronchial microbiology brush. Cultures from these specimens were used to determine the appropriate antibiotic. A second control group of 20 patients was treated with systemic antibiotics alone. Both systemic and aerosolized antibiotics were administered in 20 patients. A statistically significant improvement in clinical, and ventilatory functions was recorded in the first group compared to the second. Nebulized antibiotics used as adjunctive therapy in association with systemic antibiotics may offer a therapeutic advantage in chronic suppurative lung diseases.

Formation of thiazoles, thiazines, and thiadiazines from 1-phthalazine thiosemicarbazides as potential anticonvulsants.

3-Substituted-4-oxothiazolin-2-yl-(1-phthalazinyl)hydrazones, 3-substituted-4-oxo-5,6-dihydro-1,3-thiazin-2-yl-(1-phthalazinyl)hydrazones, and 2-substituted-amino-5-oxo-4-(1-phthalazinyl)-6-hydro-1,3,4-thiadiazines were prepared and tested for their anticonvulsant activity. Some compounds showed weak to moderate anticonvulsant activity.