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Synthesis of Some Novel 4-Substituted Coumarins Having Potential Biological Activity. Part 2
Abstract
Various methyl substituted coumarin carboxaldehydes have been condensed with aromatic amines to give Schiff bases. These Schiff bases have then been reacted with thioglycolic acid to give five membered cyclized products, 4-thiazolidinone substituted at 4-position of coumarins. 4-alkyl coumarin acetates have been reacted with semicarbazide or thiosemicarbazide in polyphosphoric acid to undergo condensation followed by in situ cyclization to form oxadiazoles and thiadiazoles. All the 4-substituted coumarin heterocycles have been found to possess antibacterial activity.
... Coumarin-4-acetic acid is a known compound, and synthetic methods for its synthesis are reported in literature. In the present study, we have taken two methods [22,23] as lead to synthesize variedly substituted coumarin-4-acetic acids. The methods were modified and optimized to get the best yields. ...
... Recently, due to the easy accessibility of the structural modification in this position (Garazd et al., 2005), various substitution groups such as aryl groups and heterocyclic rings were introduced to C-4 position, to get products with potentially enhanced or new activities (Mashelka and Audi, 2006;Kini et al., 2012;Sokmen et al., 2013). ...
Esculetin (6,7-dihydroxycoumarin) and its C-4 derivatives have multiple pharmacological activities, but the poor metabolic stability of these catechols has severely restricted their application in the clinic. Glucuronidation plays important roles in catechols elimination, although thus far the effects of structural modifications on the metabolic selectivity and the catalytic efficacy of the human UDP-glucuronosyltransferase (UGT) enzymes remain unclear. This study was aimed at exploring the structure-glucuronidation relationship of esculetin and its C-4 derivatives, including 4-methyl esculetin, 4-phenyl esculetin, 4-hydroxymethyl esculetin as well as 4-acetic acid esculetin. It was achieved by identifying the main human UGTs responsible for the different reactions and by careful characterization of the reactions kinetics. These catechols, with the exception of 4-acetic acid esculetin, are selectively metabolized to the corresponding 7-O-glucuronides. UGT1A6 and UGT1A9 are the two major UGTs involved in the 7-O-glucuronidation of 4-methyl esculetin and esculetin. UGT1A6 was the major contributor for 7-O-glucuronidation of 4-hydroxymethyl esculetin, while UGT1A9 played a significant role in the 7-O-glucuronidation of 4-phenyl esculetin. The results of the kinetic analyses revealed that the Km values of the compounds, in both UGT1A9 and human liver microsomes (HLM), decreased with increasing hydrophobicity of the C-4 substitutions. The outcome of this was that, C-4 hydrophobic and hydrophilic groups on 6,7-dihydroxycoumarin exhibited contrasting effects on UGT affinity. All of these findings provide helpful guidance for further structural modification of 6,7-dihydroxycoumarins with improved metabolic stability.
The American Society for Pharmacology and Experimental Therapeutics.
... Schiff base acquired broad spectrum of biological activities like antibacterial (Iqbal et al., 2007), antifungal (Mishra et al., 2005), anti-inflammatory (Sharma et al., 2002), antiproliferative (Vicini et al., 2006), antitubercular (Lourenco et al., 2007), and anticonvulsant (Ragavendran et al., 2007). The coumarin-incorporated 1,3,4-oxadiazoles have been reported as potential antimicrobial agents (Cacic et al., 2006;Mashelkar and Audi, 2006).The main idea of this work was to design mutual prodrugs which contain coumarin and 1,3,4-oxadiazole moieties, using Schiff base (C=N) as linkage group to produce synergistic antimicrobial activity. ...
A series of 3-{5-[(E)-(substituted benzylidene) amino]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-ones (4a–r) were synthesized by the reaction of 3-(5-amino]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one with different substituted benzaldehydes to form Schiff bases of coumarin-incorporated 1,3,4-oxadiazole derivatives. The structures of the compounds were confirmed on the basis of their elemental analysis and spectral data. The compounds were screened against bacterial strains Staphylococcus aureus NCTC (10418), Escherichia coli NCTC (6571), and fungal strain Candida albicans ATCC (10231). Ciprofloxacin and Ketoconazole were used as standards. The test compounds and standards were evaluated at 100 μg/ml concentration. DMF (N,N-dimethylformamide) was used as solvent and control. Most of the synthesized compounds possess significant antimicrobial activity. Compound (4m) without any substitution of the phenyl ring which is attached to 1,3,4-oxadiazole moiety showed highly significant in vitro growth inhibition against S. aureus and E. coli, while as compound (4g) with para N(CH3)2 showed highly significant in vitro growth inhibition against C. albicans.
... Most of the compounds are reported to have good to moderate activity against different bacterial strains [31]. Mashelkar et al. [32] and Mulwad et al. [33] have reported coumarin clubbed with oxadiazoles (1g, 1h) and evaluated their antibacterial activities. Most of the compounds were found to present remarkable antibacterial activity. ...
Among the plethora of heterocyclic nucleus discovered, the oxadiazoles have also been explored extensively. The oxadiazole structure has been demonstrated to bear important biological activities such as anti-cancer, anti-inflammatory, anti-tuberculosis, anti-malarial and anti-schistosomiasis etc. The presence of oxadiazole motifs in diverse types of compounds proves its importance in the field of medicinal chemistry. This review is complementary to earlier reviews and covers recent updates of various pharmacological aspects of oxadiazoles. To help the reader better know the context for these approaches, a summary of various aspects of background of related topic is presented.
The reactivity of 4-hydroxy-1-methyl-3-[(2-oxo-2H-chromen-3-yl)carbonyl]- quinolin-2(1H)-one (2), as a new asymmetric diheterocyclic ketone, towards different nucleophilic reagents, was examined. The reaction of the ketone 2 with hydrazine led to pyrazolinone 5, and excess of hydrazine pyrazolinopyrazole 7 was obtained. Treatment of the ketone 2 with 2,2-dimethoxyethanamine gave pyrrolocoumarin 12, while cyanoguanidine afforded pyrimidinone 15. Under PTC conditions, the ketone 2 was reacted with chloroacetonitrile, diethyl malonate, ethyl cyanoacetate, malononitrile, and cyanoacetamide to give coumarinyl furoquinoline 18, pyranoquinolines 20a, 20b, 21, and benzonaphthyridine 22, respectively.
alpha-Naphthol was converted into 4-methyl-2H-benzo[h]chromen-2-one by reacting with ethyl acetoacetate in the presence of bismuth trichloride. The product was oxidized to 2-oxo-2H-benzo[h]chromene-4-carbaldehyde and then condensed with aromatic primary amines to give Schiff bases 3a-d. These Schiff bases were then reacted with acid chlorides in the presence of a base in toluene to give 1,3,4-substituted 2-azetidinones.
Condensation of 7-methylcoumarin-4-carbaldehyde with different anilines affords 7-methylcoumarin-4-azadienes. The 7-methylcoumarin-4-azadienes do not undergo normal electron demand Diels-Alder reaction with N-phenylmaleimide, but react with dihydropyran, dihydrofuran, and styrene via inverse electron demand Diels-Alder reaction in the presence of anhydrous ZnCl2. The diene involves azomethine group and the aniline ring. The product is a mixture of two diastereomers in which the major diastereomer has all the hydrogens at the ring junction in cis configuration.
Emergence of resistance by bacterial and fungal stains towards existing antimicrobial agents is one of the major problem as well as motivation to synthesize a new class of antimicrobial agents possessing potent activity compared to commonly used therapy. Coumarin is the heterocyclic compound formed from benzene and pyrone ring containing oxygen and its derivatives are of wide awareness because of their diverse biological activity and clinical applications, they are remarkably effective compounds both with respect to their inhibitory activity and their favourable selectivity ratio. Coumarins are regarded as a promising class of bioactive heterocyclic compounds that exhibit a range of biological activities like anti-microbial, anti-viral, anti-diabetic, anti-cancer activity, anti-oxidant, anti-parasitic, anti-helmintic, anti-proliferative, anti-convulsant, anti-inflammatory and anti-hypertensive activities etc. The information given in this manuscript may be helpful in the further research of better antimicrobial agents having lesser microbial resistance and improved antimicrobial profile.
Two simple and efficient synthetic methods for the preparation of semicarbazide amino acid derivatives are reported. The procedures involve reaction between the carbamoyl azides of α-N-protected amino acids and hydrazine monohydrate: 4-[(alkoxycarbonylamino)(alkyl)methyl]semicarbazides 1 are obtained when hydrazine is added to the separated tetrahydrofuran (THF) solution containing the carbamoyl azide at 0 °C, whereas 1-[(alkoxycarbonylamino)(alkyl)methyl-carbamoyl]-4-[(alkoxycarbonylamino)(alkyl)methyl]semicarbazides 4 are produced by adding hydrazine directly into the final THF/aqueous buffer (KH2PO4) biphasic mixture containing the prepared carbamoyl azide at 50 °C, respectively. NMR experimental data obtained from samples dissolved in [D6]dimethyl sulfoxide suggest a dimeric association for semicarbazides 4 with intermolecular hydrogen bonds. Moreover, the ESI–MS–MS spectra reveal some interesting common features.
Methyl coumarin-4-methyl acetate on hromination in dioxane or dichloroethane as solvent resulted in sidechain bromination giving α-bromo derivative. The same reaction when carried out in acetic acid resulted in selective synthesis of 3-bromo derivatives. The α-bromo derivatives on reaction with various urea derivatives give novel nitrogen heterocycles (imidazolones) substituted at 4-position of coumarin ring. The α-bromo derivatives when reacted with various 1,2-diamino compounds yielded fused 2-pyrazinones attached at 4-position of coumarin ring. Considering the potential biological activities of other 4-substituted coumarins and biological importance of imidazoles, pyrazines, triazines and oxazines in drug synthesis, the new heterocycles were examined for antibacterial properties and have shown positive results.
An improved method of synthesis of thiazolidones is illustrated by the preparation of 2-β-naphthylimino-4-thiazolidone. The condensation products of the above thiazolidone with aldehydes and their bromine derivatives also are described. The bromine derivatives have been screened for fungicidal action and the arylidene derivatives for use as analytical reagents.
Stimulation of presynaptic D-2 dopamine receptors by B-HT 920 or by apomorphine inhibited the synthesis of dopamine in the corpus striatum of gammabutyrolactone-treated mice to about the same extent. Stimulation of postsynaptic D-2 dopamine receptors by B-HT 920 given in combination with the D-1 receptor agonist SKF38393 enhanced the motor activity of reserpine-treated mice at least as much as observed following the combined D-1/D-2 receptor agonist apomorphine. Since B-HT 920 is as effective as apomorphine in these models, B-HT 920 appears to be a full agonist at both pre- and post-synaptic D-2 dopamine receptors.