- Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis
-
A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ~100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further ~90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.
- Hong, W. David,Gibbons, Peter D.,Leung, Suet C.,Amewu, Richard,Stocks, Paul A.,Stachulski, Andrew,Horta, Pedro,Cristiano, Maria L. S.,Shone, Alison E.,Moss, Darren,Ardrey, Alison,Sharma, Raman,Warman, Ashley J.,Bedingfield, Paul T. P.,Fisher, Nicholas E.,Aljayyoussi, Ghaith,Mead, Sally,Caws, Maxine,Berry, Neil G.,Ward, Stephen A.,Biagini, Giancarlo A.,O’Neill, Paul M.,Nixon, Gemma L.
-
supporting information
p. 3703 - 3726
(2017/05/19)
-
- COMPOUNDS FOR TREATING VIRAL INFECTIONS
-
The present invention relates to small molecule compounds and their use in the treatment of diseases, in particular viral diseases, in particular hepatitis C virus (HCV).
- -
-
Page/Page column 90
(2015/11/09)
-
- Preparation of pyrido [2,3-b] pyrazine ring system via regioselective condensation reaction
-
The pyrido[2,3-b]pyrazine core structure can be found in several molecules that express biological activity. We have previously published a series of these compounds that showed erlotinib-resistant tumor inhibitor potential. The common way of their synthe
- Kékesi, László,Dancsó, András,Illyés, Eszter,Boros, Sándor,Patób, János,Greff, Zoltán,Németh, Gábor,Garamv?lgyi, Rita,Baska, Ferenc,Orfi, László,Kéri, Gy?rgy
-
p. 651 - 656
(2015/04/14)
-
- OXADIAZOLE DIARYL COMPOUNDS
-
The invention relates to compounds of formula (I): wherein R1, R2, Ra , Rb,Rc and W, have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.
- -
-
Page/Page column 55-56
(2009/05/29)
-
- Pyrrolobenzodiazepine pyridine carboxamides and derivatives as follicle-stimulating hormone receptor antagonists
-
This invention provides pyrrolobenzodiazepine pyridine carboxamides selected from those of Formula (1), which act as follicle stimulating hormone receptor antagonists. The invention also provides pharmaceutical compositions and methods of treatment utilizing the compounds of Formulae (1) and (2).
- -
-
Page/Page column 54
(2010/11/25)
-
- New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture
-
The present invention relates to carboxamide compounds of general formula I wherein the groups and residues A, B, W, X, Y, Z, R1, R2, R3 and k have the meanings given in claim 1. Moreover the invention relates to process for preparing the above mentioned carboxamides as well as pharmaceutical compositions containing at least one carboxamide according to the invention. In view of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia and diabetes.
- -
-
Page/Page column 59
(2010/02/09)
-
- Studies of Tetriary Amine Oxides. 9. Thermal Rearrangement of 1-(4-Substituted-phenyl)piperidine N-Oxides to the Corresponding N-Hydroxylamines
-
(4-Substituted - phenyl)piperidine N-oxides undergo a thermal rearrangement to O-arylhydroxylamines.Electron withdrawing substituents are essential for the rearrangement and must be ortho or para relative to the N-O function.The reaction has been found to be first order in substrate when rates were measured in dioxane, and the activation parameters were calculated.The order of reactivity in this rearrangement is NO2 >> CN > COPh > COMe > COOEt > CONH2.The rates correlate very well with ?- constants and the ρ value was positive and large (+3.6) pointing to a highly po lar activated complex with an electron-rich reaction center.All results strongly support an intramolecular cyclic mechanism.
- Khuthier, Abdul-Hussain,Al-Mallah, Khawla Y.,Hanna, Salim Y.,Abdulla, Noor-Aldeen I.
-
p. 1710 - 1713
(2007/10/02)
-
- Mesogenic Esters of the 4-(Alkylpiperidino) Benzoic Acids
-
A number of alkyl and 4-substituted phenyl 4-(4-alkylpiperidino) benzoates have been prepared and their proprties examined.
- Adomenas, P.,Sirutkaitis, R.
-
p. 269 - 276
(2007/10/02)
-