- Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies
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Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
- Soares De Melo, Candice,Singh, Vinayak,Myrick, Alissa,Simelane, Sandile B.,Taylor, Dale,Brunschwig, Christel,Lawrence, Nina,Schnappinger, Dirk,Engelhart, Curtis A.,Kumar, Anuradha,Parish, Tanya,Su, Qin,Myers, Timothy G.,Boshoff, Helena I. M.,Barry, Clifton E.,Sirgel, Frederick A.,Van Helden, Paul D.,Buchanan, Kirsteen I.,Bayliss, Tracy,Green, Simon R.,Ray, Peter C.,Wyatt, Paul G.,Basarab, Gregory S.,Eyermann, Charles J.,Chibale, Kelly,Ghorpade, Sandeep R.
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p. 719 - 740
(2021/02/03)
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- Compounds Based on a Triethyl- or Trimethoxybenzene Scaffold Bearing Pyrazole, Pyridine, and Pyrimidine Groups: Syntheses and Representative Binding Studies towards Carbohydrates
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Pyrazole-based artificial receptors have often been used in the recognition of ions, but in the area of sugar recognition the potential of pyrazole-based recognition groups has only been rarely examined. In this paper we describe the syntheses of twelve n
- Koch, Niklas,Seichter, Wilhelm,Mazik, Monika
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p. 2757 - 2767
(2016/08/31)
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- LRRK2 INHIBITORS
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Provided herein are compounds that inhibit or partially inhibit the activity of leucine rich repeat kinases. Also provided herein are methods of treatment of CNS disorders comprising administration of inhibitors of leucine rich repeat kinases.
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- Piperazinylalkylpyrazole derivatives useful as selective T-type calcium channel blockers and preparation method thereof
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The present invention provides for novel piperazinylalkylpyrazole derivatives, the preparation method thereof and the selective T-type calcium channel blocking activity thereof. Particularly, it provides a piperazinylalkylpyrazole derivative as represente
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Page/Page column 5
(2008/06/13)
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- Piperazinylalkylpyrazole derivatives useful as selective T-type calcium channel blockers and preparation method thereof
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The present invention provides for novel piperazinylalkylpyrazole derivatives, the preparation method thereof and the selective T-type calcium channel blocking activity thereof. Particularly, it provides a piperazinylalkylpyrazole derivative as represente
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Page/Page column 3
(2008/06/13)
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- TRICYCLIC LACTAM DERIVATIVES, THEIR MANUFACTURE AND USE AS PHARMACEUTICAL AGENTS
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Objects of the present invention are the compounds of formula (I), their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.
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Page/Page column 28-29
(2008/06/13)
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- Benzimidazole derivatives and their use as KDR kinase protein inhibitors
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The invention discloses and claims benzimidazole compounds of formula (I): wherein X is C—R2; Y is C—R2 or C—R3; W and Z are each C—R3; R1 is an optionally substituted aryl, heteroaryl or a saturated 5- or 6-membered monocyclic heterocyclic radical or a b
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- Porphyrins with four azole substituents in meso positions: X-ray crystal structure of meso-tetrakis-(1-benzylpyrazol-4-yl)-porphyrin at 200 K
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Several new porphyrins have been prepared in improved yields using an established method which was adapted to formylpyrazoles bearing on the pyrazole N1-nitrogen protective groups. The deprotection of N-para-methoxybenzyl and SEM protected meso
- Werner, Andreas,Sanchez-Migallon, Ana,Fruchier, Alain,Elguero, Jose,Fernandez-Castano, Cristina,Foces-Foces, Concepcion
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p. 4779 - 4800
(2007/10/02)
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