The benzodiazepines (BZDs) are widely used in the treatment of central nervous system (CNS) disorders such as anxiety, insomnia and epilepsy.1) The pharmacological effects of the BZDs result from their affinity for a specific binding domain on the gamma amino butyric acid (GABA A ) receptors, known as the BZD receptor. The interaction of BZD agonists with GABA A receptor complex increases the GABA-induced chloride channel opening frequency, which results in membrane hyperpolarization, thus reducing neuronal excitability.2,3) The BZD binding sites in the brain were identified and described by radioligand receptor binding assays and originally it was found that only 1,4-BZD derivatives bind to these receptors. It has since been shown that many groups of compounds bind to the BZD receptor with high affinity, e.g., triazolopyridazines, cyclopyrrolones, quinolines and b-carbolines.4-7) Several pharmacophore models have been proposed for BZDs, and amongst all models suggested for binding to the BZD receptor at least two features are common: an aromatic ring and a coplanar proton accepting group in suitable distance (5 Å). Also, the presence of a second out-ofplane, aromatic ring could potentiate binding to the receptor. [8][9][10][11][12] On this basis, a wide variety of compounds with a chemical structure different from that of BZDs have been synthesized and tested. We recently started a wide research program aimed to design new BZD receptor ligands characterized by a higher degree of flexibility compared with classic BZD ligands. Accordingly, we reported several 1,3,4-oxadiazole derivatives which showed considerable anticonvulsant activity. [13][14][15] As part of our ongoing research program to design new anticonvulsant agents, we describe herein the synthesis and biological evaluation of a novel group of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles ( Fig. 1) with a flexible second out-of-plane aromatic ring, benzyloxy group which has all the suggested requirements for binding to the BZD receptors. Results and DiscussionChemistry The target 1,3,4-oxadiazole derivatives were synthesized according to Chart 1. Accordingly, reaction of 2-halo-2-benzyloxy benzoic acid methyl ester 1 with hydrazine hydrate in N,NЈ-dimethyleformamide (DMF) at room temperature afforded corresponding 2-halo-2-benzyloxy benzoic acid hydrazide 2 high yields (87-90%).16) The hydrazide were converted to 2-amino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazoles 3 using cyanogen bromide in methanol (71-90%).17) 5-(2-Halo-2-benzyloxyphenyl)-2-mercapto-1,3,4-oxadiazole 4 was prepared by the reaction of hydrazide 2 with carbon disulfide under basic condition (60-70%). 18)Sonication of compound 5 in the presence of suitable alkyl halide in alkaline media afforded 2-alkylthio-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 5a-f (58-90%). 19)Treatment of hydrazide 2 with phenylisothiocyanate followed by reaction with KI/I 2 in alkaline hydro-ethanol gave 2-anilino-5-(2-halo-2-benzyloxyphenyl)-1,3,4-oxadiazole 7 (57-80%).20) The compounds we...
Novel Antiplatelet N‐1 substituted indole‐hydrazones.
A series of 2-substituted-4,6-diaminipyrimidine derivatives were synthesized and evaluated for their dihydrofolate reductase (DHFR) inhibitory activity. Saturation transfer difference (STD) 1 H-NMR experiments were used to probe the binding characteristics of the compounds with human DHFR enzyme. The most potent molecules, 12 and 15, in enzyme assay study showed the best results in STD experiments indicating their intimate interaction with the receptor. The docking studies were followed to explain the structural basis for the observed interaction between the ligands and DHFR. All the compounds were also assayed in vitro for their growth inhibitory activity on MCF-7, HepG2, SKHep1, and Hela tumor cell lines. Compounds 16, 17, and 22 demonstrated the most potent in vitro anti-proliferative activity among the others.Key words diaminopyrimidine; dihydrofolate reductase inhibitory activity; synthesis Interfering with folate metabolism in cancerous cells could provide a useful mean in cancer chemotherapy as a result of the inhibition of the biosynthesis of nucleic acid precursors.
Background and purpose: A group of thiosemicarbazones were prepared and their structures were confirmed by spectroscopic methods such as IR and H-NMR, mass spectrometry and also analytical method like elemental analysis. The synthesized semicarbazones were then assessed for their inhibitory activity against bacterial strains including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Bacillus cereus, Salmonella species, Enterobacter faecalis, methicillin-resistant Staphylococcus aureus , and fungi such as Candida albicans and Aspergillus niger . Experimental approach: The schiff bases of isatin ( 2a - j ) were prepared by a condensation reaction between thiosemicarbazide and substituted N-aryl isatins leading to the desired thiosemicarbazones with exquisite purity. Findings / Results: The results disclosed that all compounds have noticeable inhibitory activity. Compounds 2a , 2b , 2c , 2g , and 2h were among the most potent derivatives against Gram negative bacteria and fungi. Besides, the activity of theses compounds were tested against Mycobacterium bovis bacillus Calmette-Guerin ( M. bovis BCG). The antimycobacterial activity indicated compounds 2e and 2j are highly active against M. bovis BCG (minimum inhibitory concentration < 3.9 μg/mL). Among fluorinated structures, compounds 2a and 2j showed the best activities against M. bovis BCG. Conclusion and implications: To sum up, amongst the 10 synthesized compounds, fluorinated derivatives exhibited remarkable activities against both gram negative strains and candida albicans microorganism. Therefore, they should be considered as a clue for further modifications in next investigations. Furthermore, inserting a small/medium size halogen atom with electron-withdrawing and lipophilic properties increases anti- salmonella activity of these compounds and moreover 2-halogenated semithiocarbazones presented promising antimycobacterial activity.
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