- New diarylsulfonamide inhibitors of Leishmania infantum amastigotes
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New drugs against visceral leishmaniasis with mechanisms of action differing from existing treatments and with adequate cost, stability, and properties are urgently needed. No antitubulin drug is currently in the clinic against Leishmania infantum, the causative agent of visceral leishmaniasis in the Mediterranean area. We have designed and synthesized a focused library of 350 compounds against the Leishmania tubulin based on the structure-activity relationship (SAR) and sequence differences between host and parasite. The compounds synthesized are accessible, stable, and appropriately soluble in water. We assayed the library against Leishmania promastigotes, axenic, and intracellular amastigotes and found 0, 8, and 16 active compounds, respectively, with a high success rate against intracellular amastigotes of over 10%, not including the cytotoxic compounds. Five compounds have a similar or better potency than the clinically used miltefosine. 14 compounds showed a host-dependent mechanism of action that might be advantageous as it may render them less susceptible to the development of drug resistance. The active compounds cluster in five chemical classes that provide structure-activity relationships for further hit improvement and facilitate series development. Molecular docking is consistent with the proposed mechanism of action, supported by the observed structure-activity relationships, and suggests a potential extension to other Leishmania species due to sequence similarities. A new family of diarylsulfonamides designed against the parasite tubulins is active against Leishmania infantum and represents a new class of potential drugs with favorable cost, stability, and aqueous solubility for the treatment of visceral leishmaniasis (VL). These results could be extended to other clinically relevant species of Leishmania spp.
- González, Myriam,Alcolea, Pedro José,álvarez, Raquel,Medarde, Manuel,Larraga, Vicente,Peláez, Rafael
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- Photocatalytic C-H Amination of Aromatics Overcoming Redox Potential Limitations
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We report the photocatalytic C-H amination of aromatics overcoming redox potential limitations. Radical cations of aromatic compounds are generated photocatalytically using Ru(phen)3(PF6)2, which has a reduction potential at a high oxidation state (Ered(RuIII/RuII) = +1.37 V vs SCE) lower than the oxidation potentials of aromatic substrates (Eox = +1.65 to +2.27 V vs SCE). The radical cations are trapped with pyridine to give N-arylpyridinium ions, which were converted to aromatic amines.
- Ikarashi, Gun,Kano, Naokazu,Morofuji, Tatsuya
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supporting information
p. 2822 - 2827
(2020/04/16)
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- Pyridyl Radical Cation for C?H Amination of Arenes
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Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp2)?H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N?X pyridinium reagents mediated by visible light.
- R?ssler, Simon L.,Jelier, Benson J.,Tripet, Pascal F.,Shemet, Andrej,Jeschke, Gunnar,Togni, Antonio,Carreira, Erick M.
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supporting information
p. 526 - 531
(2019/01/04)
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- Direct and practical synthesis of primary anilines through iron-catalyzed C-H bond amination
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The direct C-H amination of arenes is an important strategy to streamline the discovery and preparation of functional molecules. Herein, we report an operationally simple arene C-H amination reaction that, in contrast to most literature precedent, affords directly the synthetically versatile primary aniline products without relying on protecting group manipulations. Inexpensive Fe(II)-sulfate serves as a convenient catalyst for the transformation. The reaction tolerates a wide scope of arenes, including structurally complex drugs. Importantly, the arene substrates are used as limiting reagents in the transformation. This operationally simple transformation should considerably accelerate the discovery of medicines and functional molecules.
- Legnani, Luca,Cerai, Gabriele Prina,Morandi, Bill
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p. 8162 - 8165
(2018/05/22)
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- PYRIDYL-THIAZOLYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to thiazole I and its therapeutic and prophylactic uses, wherein the variables Rz, Q, J, R1, R3, R5, and R6 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 38
(2012/06/01)
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- BISTHIAZOLE INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to bisthiazole I and its therapeutic and prophylactic uses, wherein the variables A, R5, R6, and R7 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.
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Page/Page column 55
(2012/06/01)
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- BENZOTHIAZOLYL INHIBITORS OF PRO-MATRIX METALLOPROTEINASE ACTIVATION
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This invention relates to benzothiazole (formula I) and its therapeutic and prophylactic uses, wherein the variables Rz, Q, J, R1, R3, R5, and R6 are defined in the specification. Disorders treated an
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Page/Page column 35
(2012/12/13)
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- Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3- triazoles
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Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of arom
- Bakunov, Stanislav A.,Bakunova, Svetlana M.,Wenzler, Tanja,Ghebru, Maedot,Werbovetz, Karl A.,Brun, Reto,Tidwell, Richard R.
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experimental part
p. 254 - 272
(2010/05/02)
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- BENZOPYRAN DERIVATIVES
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Benzopyran derivatives (I) (R = phenyl, alkoxycarbonyl, alkylcarbonyl, CONH2, CONH(alkyl), CON(alkyl)2, CN or alkoxycarbonylamino; R2 = alkyl, alkoxy, polyfluoroalkoxy, OH or CF3SO2O; each of R4 and R5 independently = H, halogen, polyfluoroalkyl, polyfluo
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- Benzopyran derivatives
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The invention relates to novel benzopyran derivatives of formula I, their N-oxides and pharmaceutically acceptable salts thereof. The compounds are endowed with enhanced selectivity for alpha1-adrenergic receptors and a low activity in lowering blood pressure. The compounds are useful in the treatment of obstructive syndromes of the lower urinary tract, including benign prostatic hyperplasia (BPH), and in the treatment of lower urinary tract symptoms (LUTS), neurogenic lower urinary tract dysfunction (NLUTD), and other conditions.
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- N-acyl anilines, useful for gastro-enterological disorders
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This invention relates to novel N-acyl anilines, to a process for their preparation and to pharmaceutical compositions containing them. The N-acyl anilines are obtained by condensing a substituted aniline with an aminolower alkyl carboxylic acid or a functional derivative thereof. The compounds of the invention have therapeutic utility namely in the gastro-enterologic field.
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- Azo pigments derived from 2-hydroxy-3-carboxynaphthalene containing a substituted or unsubstituted phthalimide
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Azo pigments derived from 2-hydroxy-3-carboxy-naphthalene and containing a substituted or unsubstituted phthalimide radical. The majority give red colorations and due to their excellent fastness properties are particularly valuable for use in surface coatings and resins.
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