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      Drug Design, Development and Therapy (submit here)

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      Synthesis, characterization, and antimicrobial evaluation of novel 5-benzoyl- N-substituted amino- and 5-benzoyl- N-sulfonylamino-4-alkylsulfanyl-2-pyridones


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          The present research describes the synthesis of novel 5-benzoyl- N-substituted-amino- and 5-benzoyl- N-sulfonylamino-4-alkylsulfanyl-2-pyridones 5ac and 6ac via the reaction of 2-benzoyl-3,3-bis(alkylthio)acrylonitriles 2ac with N-cyanoacetohydrazide 3 and cyanoaceto- N-phenylsulfonylhydrazide 4, respectively. Also, the reactivity of the compounds 5ac toward hydrazine hydrate to give product 1 H-pyrazolo[4,3- c]pyridine derivative 7 was studied. In addition, the reactivity of the 2ac toward 1-cyanoacetyl-4 arylidenesemicarbazides 8ac afforded 3,5-dihydro[1,2,4]triazolo[1,5- a]pyridine-6-carbonitrile derivatives ( 1214) ac, which reacted with hydrazine hydrate to give 3 H-pyrazolo[4,3- c][1,2,4]triazolo[1,5- a]pyridine-6-carbonitrile derivatives 15ac. The structures of the new products were characterized based on 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, infrared, mass-spectroscopy, and elemental analyses. The products were screened in vitro for their antibacterial and antifungal activity properties.

          Most cited references34

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          In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity.

          With the development of newer antifungal agents with activity against both yeasts and filamentous fungi, there is an increased need to develop and standardize in vitro assays that will evaluate the activity of antimycotics against filamentous fungi. In vitro analysis of antifungal activity of these agents would also allow for the comparison between different antimycotics, which in turn may clarify the reasons for lack of clinical response or serve as an effective therapy for patients with chronic infection. To determine the in vitro susceptibility of fungal organisms to ciclopirox, terbinafine, ketoconazole and itraconazole and to evaluate the in vitro activity and mode of interaction of ciclopirox in combination with either terbinafine or itraconazole. In the minimum inhibitory concentration (MIC) study 133 strains were evaluated, including dermatophytes (110 strains; 98 from Trichophyton spp.), Candida spp. (14 strains) and nondermatophyte moulds (nine strains). In vitro susceptibility testing was conducted in microbroth dilutions based on the National Committee for Clinical Laboratory Standards (NCCLS) M27-A proposed standard. The testing MIC ranges were 0.003-2 microg mL-1 for ciclopirox and terbinafine, and 0.06-32 microg mL-1 for itraconazole and ketoconazole. For inoculum preparation, dermatophytes were grown on Heinz oatmeal cereal agar slants. Inoculum suspensions of dermatophytes were diluted in RPMI 1640 (Sigma-Aldrich) with the desired final concentration being 2-5 x 103 c.f.u. mL-1. Once inoculated, the microdilution plates were set up according to the NCCLS M27-A method, incubated at 35 degrees C, and read visually following 7 days of incubation. For azole agents, the MIC was the lowest concentration showing 80% growth inhibition; for terbinafine and ciclopirox, the MIC was the lowest concentration showing 100% growth inhibition. In the synergy studies, 29 strains from nondermatophyte species were evaluated using a checkerboard microdilution method. The concentrations tested were: 0 and 0.06-32 microg mL-1 for itraconazole, and 0 and 0.003-4 microg mL-1 for both terbinafine and ciclopirox. Modes of interaction between drugs were classified as synergism, additivism, antagonism or indifference based on fractional inhibitory concentration index values (FIC index). Synergism was defined as an FIC index of or = 2.0. The drug combination was interpreted as indifferent if neither of the drugs had any visible effect on the presence of the other drug. In the MIC study, the dermatophyte MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.04 +/- 0.02), terbinafine (0.04 +/- 0.23), itraconazole (2.28 +/- 7.42) and ketoconazole (0.83 +/- 1.99). The yeast MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.05 +/- 0.02), terbinafine (1.77 +/- 0.58), itraconazole (0.18 +/- 0.27) and ketoconazole (0.56 +/- 0.60). The non-dermatophyte fungi MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (1.04 +/- 2.62), terbinafine (1.04 +/- 0.95), itraconazole (17.87 +/- 16.75) and ketoconazole (10.69 +/- 13.09). In the synergy study, with ciclopirox in combination with terbinafine, mainly a synergistic or additive reaction was observed; there were no cases of antagonism. For ciclopirox in combination with itraconazole, there were some instances of additivism or synergism, with indifference in the majority of instances; there were no cases of antagonism. In vitro susceptibility testing indicates that ciclopirox may have a broad antimicrobial profile including dermatophytes, yeasts and other nondermatophytes. Terbinafine is extremely potent against dermatophytes. In vitro evaluation of activity of ciclopirox and terbinafine suggests many instances of synergy or additivism; for ciclopirox and itraconazole there may be indifference, synergy or additivism.
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            The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors.

            Many attempts have been made to prepare analogs of 4-quinolone antibacterial agents bearing novel ring systems, which might retain the favorable properties of these widely used antibacterial agents and at the same time increase activity against multidrug-resistant bacteria, streptococci, and anaerobic microorganisms. One such attempt involved bioisosteric exchange of the 1-N atom and 4a-C atom of naphthyridones, quinolones, and benzoxazines to produce a family of highly active pyridopyrimidines, quinolizines, and ofloxacin bioisosteres. These new antibacterial agents have been named collectively as the 2-pyridones. Many hundreds of 2-pyridones have been synthesized and evaluated in vitro and in vivo, and selected members are advancing toward human clinical trials. Preparation of these bioisosteres required the development of enabling chemistry, as previous methods were unsuccessful in producing the needed core structures. This review compares the structure-activity relationships of these agents with known trends among 4-quinolones, from which it is seen that there are many parallels, but also some significant departures as well. Generally, 2-pyridones are more highly active in vitro and in vivo and more water soluble than comparable 4-quinolones. These properties are posited to arise from electronic and conformational alternations in these new substances. Selected members show excellent pharmacodynamic properties, justifying the view that this is a very promising new class of totally synthetic antibacterial agents.
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              Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials.

              A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                28 November 2017
                : 11
                : 3389-3399
                [1 ]Department of Chemistry, Faculty of Science, Helwan University, Helwan
                [2 ]National Institute of Laser Enhanced Sciences (NILES), Cairo University, Giza, Egypt
                [3 ]Department of Biological Sciences, University College of Duba, Tabuk University, Tabuk
                [4 ]Department of Biological Sciences, Faculty of Science, Al-Baha University, Al-Baha, Saudi Arabia
                [5 ]Department of Mycology and Mycotoxins, Animal Health Research Institute, Agriculture Research Center, Giza, Egypt
                Author notes
                Correspondence: Galal Elgemeie, Tel +20 10 0151 0203, Fax +20 22 555 2468, Email elgemeie@ 123456yahoo.com
                © 2017 Elgemeie et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                amino-2-pyridones,n-cyanoacetohydrazide,cyanoaceto-n-phenylsulfonylhydrazide,2-benzoyl-3,3-bis(alkylthio)acrylonitriles,5-benzoyl-n-sulfonylamino-4-alkylsulfanyl-2-pyridones,5-benzoyl-n-substituted-amino-4-alkylsulfanyl-2 pyridones,antimicrobial activity


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