ABSTRACT
Several compounds of great pharmacological interest contain the triazole and imidazole rings. In order to find new drugs with antileishmanial activity we have synthesized and evaluated new imidazole and triazole compounds carrying either the carbaldehyde or the difluoromethylene functionalities against promastigote forms of Leishmania amazonensis. Among the compounds tested difluoromethylene azoles 4b and 8f have inhibited the parasite growth significantly. Our results show that the introduction of the difluoromethylene moieties has turned the inactive carbaldehydes into active antileishmanial compounds.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Azoles/chemical synthesis , Azoles/pharmacology , Leishmania mexicana/drug effects , Animals , Antiprotozoal Agents/chemistry , Azoles/chemistry , Female , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
The molecules of ethyl 5-amino-1-(4-cyanophenyl)-1H-imidazole-4-carboxylate, C13H12N4O2, are linked into a chain of alternating R(2)2(10) and R(4)4(34) rings by a combination of N-H...N and C-H...N hydrogen bonds. In ethyl 5-amino-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate, C12H12ClN3O2, where the ethyl group is disordered over two sets of sites, a combination of N-H...O, N-H...N, C-H...N and C-H...pi(arene) hydrogen bonds links the molecules into complex sheets. Two intermolecular hydrogen bonds, one each of N-H...N and C-H...O types, link the molecules of ethyl 5-amino-1-(2,6-difluorophenyl)-1H-imidazole-4-carboxylate, C12H11F2N3O2, into a continuous three-dimensional framework structure.
Subject(s)
Carboxylic Acids/chemistry , Imidazoles/chemistry , Amination , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular ConformationABSTRACT
The aim of this work was to describe the synthesis, the in vitro anti-Mycobacterium tuberculosis profile, and the structure-activity relationship (SAR) study of new N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a-l). The reactions of aromatic amine hydrochlorides with diazomalonaldehyde (1) produced several N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a-l) in moderate-to-good yields. In order to investigate the influence of the difluoromethylene group on the anti-Mycobacterium activity of these compounds, fluorination of triazoles with DAST converted the corresponding carbaldehyde compounds into new difluoromethyl derivatives (4a-l) in excellent yield. Characterization of all compounds was achieved by spectroscopic means and additional for 1-(4-methylphenyl)-1,2,3-triazole-4-carbaldehyde, 3k by X-ray crystallography. Compounds (3a-l) and (4a-l) have been screened for the inhibitory activity against Mycobacterium tuberculosis H37Rv strain (ATCC 27294) and all of them were able to inhibit the growth of the bacterium. Interestingly, 3a and 3k exhibited the best inhibition with MIC values of 2.5mug/mL, similar to pharmaceuticals currently used in the treatment of tuberculosis. Our SAR study indicated the importance of the hydrogen bond acceptor subunit (3a-l), the position in the aromatic ring, the planarity of triazole and phenyl rings in these compounds, and a correlation between the uniform HOMO coefficient distribution and the anti-tubercular activity. The significant activity of 3a and 3k pointed them as promising lead molecules for further synthetic and biological exploration.
