ChemInform Abstract: SYNTH. UND EIGENSCHAFTEN VON CLOTRIMAZOL UND WEITEREN ANTIMYKOTISCHEN 1‐TRIPHENYLMETHYLIMIDAZOLEN

Buechel, K. H.; Draber, W.; Regel, E.; Plempel, M.

doi:10.1002/chin.197248316

Cited by 15 publications

(14 citation statements)

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“…These compounds exert their inhibitory effect by coordinately binding to the heme iron of P450-dependent enzymes with the N 3 nitrogen of the imidazole ring (1). Replacement of the imidazole ring by other heterocyles lacking this crucial nitrogen atom abolishes inhibition and induction of cytochrome P450 enzyme activity (17,23). To determine whether such substituents might retain potency against IKCa1, we generated a new series of analogs (Fig.…”

Section: Methodsmentioning

confidence: 99%

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

Wulff

Miller

Hänsel

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

569

642

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The antimycotic clotrimazole, a potent inhibitor of the intermediate-conductance calcium-activated K ؉ channel, IKCa1, is in clinical trials for the treatment of sickle cell disease and diarrhea and is effective in ameliorating the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by clotrimazole limits its therapeutic value. We have used a rational design strategy to develop a clotrimazole analog that selectively inhibits IKCa1 without blocking cytochrome P450 enzymes. A screen of 83 triarylmethanes revealed the pharmacophore for channel block to be different from that required for cytochrome P450 inhibition. The ''IKCa1-pharmacophore'' consists of a (2-halogenophenyl)diphenylmethane moiety substituted by an unsubstituted polar -electron-rich heterocycle (pyrazole or tetrazole) or a ؊C'N group, whereas cytochrome P450 inhibition absolutely requires the imidazole ring. A series of pyrazoles, acetonitriles, and tetrazoles were synthesized and found to selectively block IKCa1. TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole) inhibits the cloned and the native

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Section: Methodsmentioning

confidence: 99%

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

Wulff

Miller

Hänsel

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

569

642

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“…Details on the chemistry of the compounds used will be published elsewhere. The second group (Table 1) includes compounds related to m-(2,4-dichlorophenyl)-m-phenyl-5-pyrimidinemethanol (triarimol, I_~7) and partly to N-2-chlorotritylimidazole (clotrimazole, 20), a fungicide used in dermatology (Davenport et al, 1970;BUchel et al, 1972). Their activity is based on the inhibition of fungal sterols.…”

Section: Methodsmentioning

confidence: 98%

Studies on the antifungal action of potential steroid inhibitors

et al. 1977

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“…Bifonazole has shown excellent control of tinea corporis and tinea pedis of humans caused by Trichophyton species (Figures 5-7) (3,6,10).…”

Section: Q-mentioning

confidence: 99%

The History of Azole Chemistry

Büchel

1986

ACS Symposium Series

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Since the earliest days of agriculture, insect pests, weeds and plant diseases have been some of the major problems of agriculture. Insect pests are visible and could, at least in some cases be countered by hand removal. A certain level of weed elimination was achieved by hoeing and hand weeding, an never ending task. However, rust, powdery mildew and smut being invisible enemies, spread throughout the fields like an unpredictable fate.Thus they occupied the imagination of rural folk, and magical concepts of disease control predominated in the early days of agriculture.Until the discovery of Bordeaux mixture in 1880, farmers had no real possibility of defending their crops against the ravages of fungal diseases. Fungi had only been identified a few years previ ously as the cause of plant diseases. Apart from a few empirical measures to prevent disease, active control was not possible. Massive disease epidemics often had catastrophic social consequences. The legacy of the Irish potato famine of the 1840's can be seen even today. It is difficult to imagine the significance of the pioneer fungicides, ones based on copper, sulphur and mercury, had in their time.The organic fungicides of the dithiocarbamate and phthalimide type (e.g. Captan) were a breakthrough in this field in the nineteen thirties and forties. Although they only have protective activity and thus must be used prophylactically, they found broad applications due to their high plant compatibility and broad disease control spectrum.A further milestone in the development of fungicides was the discovery of the so-called systemic fungicides, chemicals that are taken up by the plant and transported within it. The fungicide classes found in the sixties, including the oxathiines, pyrimidines and organophosphates, are characterized by being absorbed by the leaves, often also by the seeds and roots, and being transported acropetally within the plant. These products have only a very narrow disease control spectrum. The oxathiines are active against Basidiomycetes, mainly against rusts and smuts; the pyrimidine derivatives are active against powdery mildews. The organophosphates are used for Pyricularia control in rice.

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ChemInform Abstract: SYNTH. UND EIGENSCHAFTEN VON CLOTRIMAZOL UND WEITEREN ANTIMYKOTISCHEN 1‐TRIPHENYLMETHYLIMIDAZOLEN

Cited by 15 publications

References 0 publications

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

Studies on the antifungal action of potential steroid inhibitors

The History of Azole Chemistry

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ChemInform Abstract: SYNTH. UND EIGENSCHAFTEN VON CLOTRIMAZOL UND WEITEREN ANTIMYKOTISCHEN 1‐TRIPHENYLMETHYLIMIDAZOLEN

Cited by 15 publications

References 0 publications

Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+channel,IKCa1: A potential immunosuppressant

Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+channel,IKCa1: A potential immunosuppressant

Studies on the antifungal action of potential steroid inhibitors

The History of Azole Chemistry

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Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant

Design of a potent and selective inhibitor of the intermediate-conductance Ca²⁺-activated K⁺channel,IKCa1: A potential immunosuppressant