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1.
Eur J Med Chem ; 243: 114778, 2022 Dec 05.
Article in English | MEDLINE | ID: mdl-36194937

ABSTRACT

Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. Available treatments are limited and have considerable adverse effects and questionable efficacy in the chronic stage of the disease, urgently calling for the identification of new targets and drug candidates. Recently, we have shown that impairment of glycosomal protein import by the inhibition of the PEX5-PEX14 protein-protein interaction (PPI) is lethal to Trypanosoma. Here, we report the development of a novel dibenzo[b,f][1,4]oxazepin-11(10H)-one scaffold for small molecule inhibitors of PEX5-PEX14 PPI. The initial hit was identified by a high throughput screening (HTS) of a library of compounds. A bioisosteric replacement approach allowed to replace the metabolically unstable sulphur atom from the initial dibenzo[b,f][1,4]thiazepin-11(10H)-one HTS hit with oxygen. A crystal structure of the hit compound bound to PEX14 surface facilitated the rational design of the compound series accessible by a straightforward chemistry for the initial structure-activity relationship (SAR) analysis. This guided the design of compounds with trypanocidal activity in cell-based assays providing a promising starting point for the development of new drug candidates to tackle trypanosomiases.


Subject(s)
Trypanocidal Agents , Trypanosoma brucei brucei , Trypanosoma , Membrane Proteins , Microbodies , Protein Transport/physiology , Structure-Activity Relationship , Trypanocidal Agents/pharmacology
2.
Org Lett ; 20(16): 5019-5022, 2018 08 17.
Article in English | MEDLINE | ID: mdl-30079737

ABSTRACT

4-Substituted α-trifluoromethyl azepanes C were synthesized via the ring expansion of trifluoromethyl pyrrolidines A, which were synthesized from l-proline via a regioselective ring-opening of a bicyclic azetidinium intermediate B by various nucleophiles. The regioselectivity of the ring expansion is induced by the presence of a trifluoromethyl group. The chirality of the starting material was transferred to the azepanes with high enantiomeric excess.

3.
Molecules ; 22(3)2017 Mar 19.
Article in English | MEDLINE | ID: mdl-28335499

ABSTRACT

A comprehensive survey of pathways leading to the generation of α-trifluoromethyl monocyclic piperidinic derivatives is provided (65 references). These compounds have been synthesized either from 6-membered rings e.g., pipecolic acid or lactam derivatives by introduction a trifluoromethyl group, from pyridine or pyridinone derivatives by reduction, and from 5-membered rings e.g., prolinol derivatives by ring expansion, from linear amines by cyclization or from dienes/dienophiles by [4 + 2]-cycloaddition.


Subject(s)
Amines/chemistry , Piperidines/chemical synthesis , Cyclization , Cycloaddition Reaction , Molecular Structure , Piperidines/chemistry , Pyrrolidines/chemistry , Stereoisomerism
4.
Org Lett ; 17(12): 2916-9, 2015 Jun 19.
Article in English | MEDLINE | ID: mdl-26000643

ABSTRACT

3-Substituted 2-(trifluoromethyl)piperidines B were synthesized by ring expansion of (trifluoromethyl)prolinols A, which were obtained from L-proline via an aziridinium intermediate C. The ring opening of the (trifluoromethyl)aziridinium intermediate by different nucleophiles is regio- and diastereoselective.


Subject(s)
Aziridines/chemistry , Piperidines/chemical synthesis , Proline/chemistry , Pyrrolidines/chemistry , Molecular Structure , Piperidines/chemistry , Stereoisomerism
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