ABSTRACT
The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1-2 µM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.
Subject(s)
Captopril , Trypanosoma brucei brucei , Trypanosoma cruzi , Captopril/pharmacology , Captopril/chemistry , Captopril/chemical synthesis , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/enzymology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , Structure-Activity Relationship , Molecular Docking Simulation , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/chemical synthesis , Molecular Structure , Leishmania/drug effects , Leishmania/enzymology , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , HumansABSTRACT
We report the synthesis of two novel azaperhydroazulene tropane-hederacine chimeras A and B, which contain an 8-azabicyclo[3.2.1]octane ring and a 7-azabicyclo[4.1.1]octane ring, respectively. The synthesis of both chimeras was achieved by epoxide ring opening and was governed by the stereochemistry of the hydroxy-epoxide unit. Finally, a density functional theory study was conducted to explain the regioselectivity of the cyclization and the importance of the stereochemistry of the hydroxyl group.
ABSTRACT
We communicate a versatile synthetic approach to C-3 disubstituted 2-oxa-5-azabicyclo[2.2.1]heptanes as carbon-atom bridged morpholines, starting with 4R-hydroxy-l-proline as a chiron. Attaching an acetic acid moiety on the C-3 carbon of the 2-oxa-5-azabicyclo[2.2.1]heptane core reveals the framework of an embedded γ-amino butyric acid (GABA). Variations in the nature of the substituent on the tertiary C-3 atom with different alkyls or aryls led to backbone-constrained analogues of the U.S. Food and Drug Administration-approved drugs baclofen and pregabalin.
Subject(s)
Amino Acids , Heptanes , Carbon , Heptanes/chemistry , Proline , StereoisomerismABSTRACT
We describe the synthesis of a series of 3-t-butyl 5-aminopyrazole p-substituted arylamides as inhibitors of serine-threonine25 (STK25), an enzyme implicated in the progression of non-alcoholic fatty liver disease (NAFLD). Appending a p-N-pyrrolidinosulphonamide group to the arylamide group led to a 'first-in kind' inhibitor with IC50 = 228 nM. A co-crystal structure with STK 25 revealed productive interactions which were also reproduced using molecular docking. A new series of triazolo dihydro oxazine carboxamides of 3-t-butyl 5-aminopyrazole was not active against STK25.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Intracellular Signaling Peptides and Proteins , Molecular Docking Simulation , Non-alcoholic Fatty Liver Disease/drug therapy , Oxazines , Protein Serine-Threonine Kinases , Serine , Threonine , X-RaysABSTRACT
We report the synthesis of two novel bridged morpholine-proline chimeras 4 and 5, which represent rigid conformationally locked three-dimensional structures wherein the lone pairs of electrons on oxygen and nitrogen are oriented in spatially different "east-west" and "north-west" directions, respectively. In combination with the presence of a carboxylic acid, the electronic features of these compounds may be useful in the context of peptidomimetic design of biologically relevant compounds. Quantitative estimates of the basicity of the nitrogen atoms were obtained using conceptual density functional theory analysis.
ABSTRACT
We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.