- Development of inhibitors against mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches
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Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.
- Whitehouse, Andrew J.,Thomas, Sherine E.,Brown, Karen P.,Fanourakis, Alexander,Chan, Daniel S.-H.,Libardo, M. Daben J.,Mendes, Vitor,Boshoff, Helena I. M.,Floto, R. Andres,Abell, Chris,Blundell, Tom L.,Coyne, Anthony G.
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supporting information
p. 7210 - 7232
(2019/08/20)
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- SUBSTITUTED 1-AMINOPHTHALAZINE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC APPLICATION THEREOF
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The invention concerns 1-amino-phthalazine derivatives of general formula (I): Wherein A, B, L, R, R1, R2, R3, R4, R5 and R7 are as defined herein. The invention also concerns the preparation of said compounds and their therapeutic use.
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Page/Page column 30
(2009/05/28)
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- Pyrazolyl derivatives, preparation process and intermediates of this process as medicinal products and pharmaceutical compositions containing them
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The present invention relates to the novel derivatives of formula (I) in which A is, if it is present, a (C1-C6) alkyl, a (C3-C6) alkenyl, a (C3-C6) alkynyl, a (C3-C7) cycloalkyl or a (C5-C7) cycloalkenyl, R1 is an NR6R7, (C4-C7) azacycloalkyl, (C5-C7) azacycloalkenyl, (C5-C9) azabicycloalkyl or (C5-C9) azabicycloalkenyl group; A-R1 is such that the nitrogen of R1 and the nitrogen in the 1-position of the pyrazole are necessarily separated by at least two carbon atoms, R3 is an H, halogen, OH, SH, NH2, ORc, SRc, SORa, SO2Ra, NHCHO, NRaRb, NHC(O)Ra, NHC(S)Ra or NHSO2Ra, R4 is an aryl or heteroaryl; and R5 is an H, halogen, CF3, CHF2, CH2F, linear or branched (C1-C6) alkyl or (C3-C7) cycloalkyl to their racemates, enantiomers and diastereoisomers and to their mixtures, their tautomers and to their pharmaceutically acceptable salts.
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Page/Page column 62
(2008/06/13)
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- Rigidified acetylcholine mimics: Conformational requirements for binding to neuronal nicotinic receptors
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Rigidified derivatives have been designed and synthesized assuming the g+t conformer of acetylcholine (N-C-C-O=+60°, C-C-O-C=180°) as active conformation for binding to cytisine sensitive neuronal nicotinic receptors. The SAR of the compounds evaluated, along with those of more flexible analogues, support the g+t conformer hypothesis and highlight the stringent steric limitation of this nicotinic receptor sub-type. Compound 3e has low μM affinity for cytisine sensitive nicotinic receptor binding sites while being selective with regard to the α-bungarotoxin sensitive subclass. We also report few compounds with μM affinity for the α-bungarotoxin sensitive subclass.
- Villeneuve, Gerald,Cecyre, Danielle,Lejeune, Helene,Drouin, Marc,Lan, Ruoxi,Quirion, Remi
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p. 3847 - 3851
(2007/10/03)
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- Dermal anesthetic agents
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The present invention relates to new aminoindane piperidine compounds, the method of using aminoindane compounds as local anesthetics, said compounds having particularly valuable properties as dermal and topical anesthetics in mammals, including man, as well as compositions containing said compounds.
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