- Development of a method for the quantification of clotrimazole and itraconazole and study of their stability in a new microemulsion for the treatment of sporotrichosis
-
Sporotrichosis occurs worldwide and is caused by the fungus Sporothrix brasiliensis. This agent has a high zoonotic potential and is transmitted mainly by bites and scratches from infected felines. A new association between the drugs clotrimazole and itraconazole is shown to be effective against S. brasiliensis yeasts. This association was formulated as a microemulsion containing benzyl alcohol as oil, Tween 60 and propylene glycol as surfactant and cosurfactant, respectively, and water. Initially, the compatibility between clotrimazole and itraconazole was studied using differential scanning calorimetry (DSC), thermogravimetric analysis (TG), Fourier transform infrared spectroscopy (FTIR), and X-ray powder diffraction (PXRD). Additionally, a simple and efficient analytical HPLC method was developed to simultaneously determine the concentration of clotrimazole and itraconazole in the novel microemulsion. The developed method proved to be efficient, robust, and reproducible for both components of the microemulsion. We also performed an accelerated stability study of this formulation, and the developed analytical method was applied to monitor the content of active ingredients. Interestingly, these investigations led to the detection of a known clotrimazole degradation product whose structure was confirmed using NMR and HRMS, as well as a possible interaction between itraconazole and benzyl alcohol.
- Ferreira, Patricia Garcia,de Souza Lima, Carolina Guimar?es,Noronha, Letícia Lorena,de Moraes, Marcela Cristina,de Carvalho da Silva, Fernando,Vi?osa, Alessandra Lifsitch,Futuro, Débora Omena,Ferreira, Vitor Francisco
-
supporting information
(2019/07/04)
-
- Facile synthesis of phthalides from methyl ortho-iodobenzoates and ketones via an iodinemagnesium exchange reaction using a silylmethyl Grignard reagent
-
Phthalides have been easily prepared by the treatment of methyl o-iodobenzoates with a silylmethyl Grignard reagent in the presence of ketones. The electron-withdrawing ester moiety of methyl o-iodobenzoates and the low nucleophilicity of the silylmethyl Grignard reagent prompted a smooth iodinemagnesium exchange reaction, at room temperature, without affecting the ester moiety or resulting in an undesired reaction with electrophilic ketones. This simple method, wherein special control of the reaction temperature was unnecessary, has allowed the synthesis of various phthalides, including a phenolphthalein derivative.
- Nakamura, Yu,Yoshida, Suguru,Hosoya, Takamitsu
-
supporting information
p. 858 - 861
(2017/06/13)
-
- Triphenylbutanamines: Kinesin spindle protein inhibitors with in vivo antitumor activity
-
The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit Kiapp ≥ 10 nM and GI50 ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.
- Wang, Fang,Good, James A. D.,Rath, Oliver,Kaan, Hung Yi Kristal,Sutcliffe, Oliver B.,MacKay, Simon P.,Kozielski, Frank
-
supporting information; experimental part
p. 1511 - 1525
(2012/04/10)
-
- Protolytic defluorination of trifluoromethyl-substituted arenes
-
A series of trifluoromethyl-substituted arenes were studied in their reactions with Bronsted superacids. The products from these reactions suggest the formation of reactive electrophiles, such as carbocations, acylium cations or equivalent electrophilic species. As such, Friedel-Crafts-type reactions occur between these species and arene nucleophiles. NMR studies were done, and the results suggest the formation of an acyl group from the trifluoromethyl groups in the superacid.
- Kethe, Anila,Tracy, Adam F.,Klumpp, Douglas A.
-
experimental part
p. 4545 - 4549
(2011/07/29)
-
- Novel inhibitors of the gardos channel for the treatment of sickle cell disease
-
Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of 10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.
- McNaughton-Smith, Grant A.,Burns, J. Ford,Stocker, Jonathan W.,Rigdon, Gregory C.,Creech, Christopher,Arlington, Susan,Shelton, Tara,De Franceschi, Lucia
-
p. 976 - 982
(2008/12/20)
-
- A new method for the preparation of 2-chlorotrityl resin and its application to solid-phase peptide synthesis
-
2-Chlorotritylchloride (2-CTC) resin was prepared efficiently from 1% DVB-crosslinked polystyrene resin and 1-chloro-2-(dichloro(phenyl)methyl)benzene, which was easily obtained from 2-chlorobenzophenone. This 2-CTC resin showed excellent properties as a support for solid-phase peptide synthesis. Four peptide fragments were obtained in high purity using the resin.
- Lee, Tae-Kyung,Ryoo, Sun-Jong,Lee, Yoon-Sik
-
p. 389 - 391
(2008/02/03)
-
- METHOD OF TREATING NEUROLOGICAL DISORDERS USING CLOTRIMAZOLE AND DERIVATIVES THEREOF
-
Methods and pharmaceutical compositions are disclosed for treating neurological disorders, such as Huntington's disease or Alzheimer's disease. The methods involve the administration of a triarylmethane compound, such as clotrimazole, or a salt thereof.
- -
-
Page/Page column 51; 52
(2008/06/13)
-
- Triaryl methane derivatives as antiproliferative agents
-
Clotrimazole (CLT) 1, a synthetic anti-fungal imidazole derivative, inhibits tumor cell proliferation and angiogenesis. In the current study, flow cytometric analysis demonstrated that the decrease in tumor cell growth by CLT 1 was associated with inhibition of cell cycle progression at the G 1-S phase transition, resulting in G0-G1 arrest. A series of CLT 1 analogues has been generated in order to develop CLT 1 derivatives that are devoid of the imidazole moiety which is responsible for the hepatoxicity associated with CLT 1 while retaining CLT 1 efficacy. The majority of these analogues demonstrate in vitro antiproliferative activity ranging from submicromolar to micromolar concentrations.
- Al-Qawasmeh, Raed A.,Lee, Yoon,Cao, Ming-Yu,Gu, Xiaoping,Vassilakos, Aikaterini,Wright, Jim A.,Young, Aiping
-
p. 347 - 350
(2007/10/03)
-
- Non-peptide inhibition of T-lymphocyte activation and therapies related thereto
-
Compounds, preparations and methods for immunosuppressive treatment of autoimmune disorders, graft rejection and/or graft/host disease. Therapeutically effective amounts of certain substituted triarylmethane compounds, such as 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole, are administered to mammalian patients to selectively inhibit the calcium-activated K + channel (IKCa1) in lymphocytes, monocytes, macrophages, platelets or endothelial cells without concomitant inhibition of P450-dependent enzyme systems, resulting in reduction of antigen-, cytokine-, or mitogen-induced calcium entry through store operated calcium channels in these cells, suppression of cytokine production by these cells, and inhibition of activation of these cells. Such inhibition of the Ca ++ activated K + channel (IKCa1) prevents the pre-Ca ++ stage of cell activation and thus causes immunosuppression and an anti-inflammatory response.
- -
-
-
- Tritylamino aromatic heterocycles and related carbinols as blockers of Ca2+-activated potassium ion channels underlying neuronal hyperpolarization
-
A series of novel aromatic tritylamino heterocycles has been synthesized and the compounds have been tested in comparison with clotrimazole for their ability to inhibit the slow afterhyperpolarization current (SlAHP) in cultured rat hippocampal pyramidal neurones. Some analogues of the clotrimazole metabolite, 2-chlorophenyl-diphenyl methanol, having different chlorination substitution in the triphenyl group have also been examined. Two compounds in particular, 3-[(2-chlorophenyl)diphenylmethylamino]pyridine (3a, UCL 1880) and 2-tritylaminothiazole (6, UCL 2027), are of special interest; they are effective blockers of the SlAHP (IC50 = 1.1-1.2 μM) and are much more selective than clotrimazole since they have less effect on the high voltage-activated Ca2+ current.
- Zunszain, Patricia A.,Shah, Mala M.,Miscony, Zena,Javadzadeh-Tabatabaie, Mazyar,Haylett, Dennis G.,Ganellin, C. Robin
-
p. 159 - 166
(2007/10/03)
-
- Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
-
The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction. Moreover, the invention relates to a method of screening a chemical compound for inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca).
- -
-
-
- Use of triaryl methane compounds for inhibiting unwanted cellular proliferation associated with inflammatory disease
-
The present invention provides a class of chemical compounds useful as efficacious drugs in the treatment of sickle cell disease and diseases characterized by unwanted or abnormal cell proliferation, and in particular inflammatory diseases associated with unwanted cellular proliferation. The active compounds are substituted triaryl methane compounds or analogues thereof where one or more of the aryl groups is replaced with a heteroaryl, cycloalkyl or heterocycloalkyl group and/or the tertiary carbon atom is replaced with a different atom such as Si, Ge, N or P, the compounds inhibit mammalian cell proliferation, inhibit the Gardos channel of erythrocytes, reduce sickle erythrocyte dehydration and/or delay the occurrence of erythrocyte sickling or deformation.
- -
-
-
- Treatment of GLC1A glaucoma with non-steroidal glucocorticoid antagonists
-
Compositions of non-steroidal glucocorticoid antagonists for treating GLC1A glaucoma and methods for their use are disclosed.
- -
-
-
- Process for preparing N-tritylimidazole compounds
-
A process for preparing N-tritylimidazole compounds of the formula: STR1 by the reaction between a tritylcarbinol derivative of the formula: STR2 and an imidazole derivative of the formula: STR3 , characterized in that the reaction is effected in the presence of a phosphorus compound of the formula: STR4
- -
-
-
