24225-89-6Relevant articles and documents
Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics
El-wahab, Hend A.A. Abd,Accietto, Mauro,Marino, Leonardo B.,McLean, Kirsty J.,Levy, Colin W.,Abdel-Rahman, Hamdy M.,El-Gendy, Mahmoud A.,Munro, Andrew W.,Aboraia, Ahmed S.,Simons, Claire
, p. 161 - 176 (2017/11/29)
Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 ?. A model generated from a 1.5 ? crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.
DIBENZO[B,F][1,4]OXAZAPINE COMPOUNDS
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, (2008/12/07)
The present invention relates to 11-(piperazin-l-yl)dibenzo[b,f][l,4]oxazapine compounds of the formula I (I) where the variables are as defined herein, their salts and pharmaceutically acceptable compositions thereof. Methods of preparing these compounds are also described. These compounds may be used in the treatment of disorders such as schizophrenia, treatment resistant schizophrenia, bipolar disorder, psychotic depression, treatment resistant depression, schizophrenia-associated depression, treatment resistant OCD, autism, senile psychosis, psychotic dementia, L-DOPA induced psychosis, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleep disorders.
Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type ii diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'- dihydro-1'H-imidazol-2'-yl)piperazines and isosteric analogues of imidazoline
Le Bihan, Ga?lle,Rondu, Frédéric,Pelé-Tounian, Agnès,Wang, Xuan,Lidy, Sandrine,Touboul, Estéra,Lamouri, Aazdine,Dive, Georges,Huet, Jack,Pfeiffer, Bruno,Renard, Pierre,Guardiola-Lema?tre, Béatrice,Manéchez, Dominique,Pénicaud, Luc,Ktorza, Alain,Godfroid, Jean-Jacques
, p. 1587 - 1603 (2007/10/03)
Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl- 4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2',4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H- imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of α2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4',5'-dihydro-1'H-imidazol-2'- yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4',5'-dihydro- 1'H-imidazol-2'-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 μmol/kg) as after ip administration and appears as a good candidate for clinical investigations.
