Manohar V. Kulkarni

Recent advances in coumarins and 1-azacoumarins as versatile biodynamic agents

Coumarins, also referred as benzopyran-2-ones, and their corresponding nitrogen counterpart, 1-azacoumarins also referred to as carbostyrils, are a family of nature-occurring lactones and lactams respectively. The plant extracts containing coumarin-related heterocycles, which were employed as herbal remedies in early days, have now been extensively studied for their biological activities. These investigations have revealed their potentials as versatile biodynamic agents. For example, coumarins with phenolic hydroxyl groups have the ability to scavenge reactive oxygen species and thus prevent the formation of 5-HETE and HHT in the arachidonic pathway of inflammation suppression. Recent in vivo studies have revealed the role of coumarins in hepatotoxicity and also in depletion of cytochrome P450. Similarly 1-azacoumarins which is part of quinoline alkaloids, are known for their diverse biological activity and recently, a 6-functionalized 1-aza coumarins are undergoing human clinical trials as an orally active anti-tumor drug in view of its farnesyl protein-inhibiting activity in the nanomolar range. Furthermore, several synthetic coumarins with a variety of pharmacophoric groups at C-3, C-4 and C-7 positions have been intensively screened for anti-microbial, anti-HIV, anti-cancer, lipid-lowering, anti-oxidant, and anti-coagulation activities. Specifically, coumarin-3-sulfonamides and carboxamides were reported to exhibit selective cytotoxicity against mammalian cancer cell lines. The C4-substituted aryloxymethyl, arylaminomethyl, and dichloroacetamidomethyl coumarins, along with the corresponding 1-azacoumarins, have been demonstrated to be potential anti-microbial and anti-inflammatory agents. To expand the structural diversity of synthetic courmarins for biological functions, attempts have also been made to attach a chloramphenicol side chain at C-3 position of courmarin. In addition, the bi- and tri-heterocyclic coumarins and 1-azacoumarins with benzofuran, furan and thiazole ring systems along with biocompatible fragments like vanillin have shown remarkable potency as anti-inflammatory agents in animal models. Photobiological studies on pyridine-fused polycyclic coumarins have highlighted their potential as thymine dimer photosensitisers and the structurally related compounds of both coumarin and carbostyrils have also been found to act via the DNA gyrase pathway in their anti-bacterial activity. Apart from the above works, the present review also addresses the potential roles of coumarins and carbostyrils as protease inhibitors, or fluorescent probes in mechanistic investigation of biochemical pathways, and their application for QSAR in theoretical studies. Though 1-Azacoumarins have received less attention as compared to coumarins in the literature, an attempt has been made to compare both the systems at various stages, so that it can spark new thoughts on synthetic methodologies, reactivity pattern and biological activities.

Synthesis and antimicrobial studies on novel sulfonamides containing 4-azidomethyl coumarin.

A series of new and novel coumarin-6-sulfonamides with a free C4-azidomethyl group have been synthesized as antimicrobials in three steps starting from 7-methyl-4-bromomethylcoumarin 1. The reaction of 1 with chlorosulfonic acid was found to yield the corresponding 6-sulfonylchloride 2, which when treated with sodium azide led to intermediate 3. The title sulfonamides 5a-y were obtained from the reaction of 3 with various aromatic amines 4 in refluxing benzene. The chemical structures of the compounds were elucidated by IR, NMR and LC-MS spectral data. All the synthesized compounds have been screened for their in vitro anti-bacterial and anti-fungal activities. Some of the compounds have been found to be active against both bacterial species at a concentration of 1 microg/mL.

Studies on Coumarins, I

4‐Bromomethylcoumarins, prepared by the reaction of phenols and 4‐bromoethyl acetoacetate, were reacted with primary aromatic amines to yield 4‐anilinomethylcoumarins. The spectral properties and antimicrobial activities against five micro‐organisms are reported.

Vibrational assignments for 7-methyl-4-bromomethylcoumarin, as aided by RHF and B3LYP/6-31G* calculations.

Infrared (4000-400 cm(-1)) and Raman (3500-50 cm(-1)) spectral measurements have been made for the solid sample of 7-methyl-4-bromomethylcoumarin. Electronic structure calculations at RHF/6-31G* and B3LYP/6-31G* levels of theory have been performed, giving equilibrium geometries, harmonic vibrational spectra and normal modes. Different orientations of bromomethyl group have yielded only two conformers, of which the most stable one lying lower from the other conformer by approximately 7.99 kJ/mol, is non-planar with no symmetry. A complete assignment of the vibrational modes, aided by the calculations, has been proposed. Coupled vibrations are manifest in many modes. Some spectral features, compared to 6-methyl-4-bromomethylcoumarin, show changes across both IR and Raman spectra, involving mainly skeletal vibrations, and to a lesser degree, methyl and bromomethyl vibrations. Low-frequency vibrations below 150 cm(-1) are assigned to lattice modes.

Synthesis of spiro(indolo-1,5-benzodiazepines) from 3-acetyl coumarins for use as possible antianxiety agents

Abstract3-Acetyl coumarins (1) when allowed react with isatin (2) gave corresponding 3-(3′-hydroxy-2′-oxo indolo) acetyl coumarins (3), which on dehydration afforded the correspondingα,β-unsaturated ketones (4). Cyclocondensation of (4) with substitutedo-phenylene diamines resulted in novel 3-coumarinyl spiro[indolo-1,5-benzodiazepines] (5). Structures of all the compounds have been established on the basis of their IR, NMR and mass spectral data and have been screened for their antimicrobial activity and antianxiety activity in mice

Click Chemistry Approach for Bis‐Chromenyl Triazole Hybrids and Their Antitubercular Activity

1,4‐Disubstituted bis‐chromenyl triazole hybrids 5a–m have been synthesized in a three‐step reaction sequence from 4‐(bromomethyl)‐2H‐chromen‐2‐ones 3a–m. The intermediate azides 4a–m underwent a regioselective 1,3‐dipolar cycloaddition with a 2H‐chromen‐2‐one linked acetylenic dipolarophile in the presence of Cu (II)/ascorbate/water/n‐butanol reaction medium. Three compounds 5h–j exhibited 6.25 μg/mL MIC against M. tuberculosis. Among the compounds screened for antifungal activity, lowest MIC of 6.25 μg/mL was observed for 5c against A. niger that also exhibited DNA cleavage observed by agarose gel electrophoresis. All the compounds were moderately active against both Gram‐positive and Gram‐negative bacterial strains. The cytotoxic effect of potent compounds on normal cells (V79 and HBL100) was assessed by MTT assay.

A click chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl triazoles as anti-tubercular agents.

A series of mono and bis-triazole coumarin hybrids 6a-u and 9a-f respectively have been synthesized using 4-(azidomethyl)-2H-chromen-2-ones 5a-i and aryl propargyl ethers 2a-c/8 employing Click chemistry modified protocol for Azide-Alkyne cycloadditions(CuAAC). Anti-tubercular screening showed moderate activity for mono aryloxy compounds 6a-u with MIC 50-100 μg/mL, whereas the bis compounds 9a-f were more effective with MICs between 0.2 and 12.5 μg/mL. Molecular modeling and 3D-QSAR measurements using CoMFA and Topomer CoMFA further supported the observed results. The bis compound 9b showed excellent activity with MIC value as low as 0.2 μg/mL.

Vibrational spectra, normal modes, ab initio and DFT calculations for 6-Chloro- and 7-Chloro-4-bromomethylcoumarins.

Vibration spectral measurements - Infrared (4000-400 cm(-1)) and Raman (3500-50 cm(-1)) spectra - have been made for the solid samples of 6-Chloro- and 7-Chloro-4-bromomethylcoumarins. Ground electronic state energies, equilibrium geometries, harmonic vibrational spectra and normal modes have been computed using ab initio - RHF/6-31G* - and DFT - B3LYP/6-31G* levels of theory. The optimization yielded three structures for each molecule, with one being a transition state structure. Of the remaining two conformers, one belongs to C(s) symmetry and the other belongs to C(1), the latter being the most stable one. The optimized dihedral angle for -CH(2)Br group is 111 degrees in agreement with X-ray diffraction results reported for the similar molecular systems. Assignment of all the observed spectral bands has been proposed. The absorptions show band pattern revealing isomer characteristics and vibrational coupling in varying degrees; the Raman spectra show structural changes associated with the rings as well as lattice modes.

Effect of Solvent Polarity on the Fluorescence Quenching of Biologically Active 5BAMC by Aniline in Binary Solvent Mixtures

The fluorescence quenching of 5, 6-benzo-4-azidomethyl coumarin (5BAMC) by aniline have been carried in different solvent mixtures of benzene (BN) and acetonitrile (AN) at room temperature by steady state fluorescence measurements. The quenching is found to be appreciable and a positive deviation from linearity was observed in the Stern-Volmer plot for the fluorophore in all the solvent mixtures. Various parameters for the quenching process have been determined using the extended S-V equation and have been found to be dependent on the solvent polarity. Further, with the use of finite sink approximation model, it is concluded that the bimolecular reactions quenching reactions are diffusion limited, and the distance parameter R′ and mutual diffusion coefficient D are estimated independently.

Estimation of dipole moments of some biologically active coumarins by solvatochromic shift method based on solvent polarity parameter, ETN

The electronic absorption and fluorescence spectra of three newly synthesized coumarin derivatives viz., 4-(5-methyl-3-furan-2-yl-benzofuran-2-yl)-7-methyl-chromen-2-one (MFBMC), 4-(5-chloro-3-furan-2-yl-benzofuran-2-yl)-6-methyl-chromen-2-one (ClFBMC) and 4-(5-methyl-3-phenyl-benzofuran-2-yl)-6-chloro-chromen-2-one (MPBClC) have been recorded at room temperature (296 K) in solvents of different polarities. The effects of the solvents upon the spectral properties are discussed. Solvatochromic correlations were used to estimate the ground-state (mu(g)) and excited-state (mu(e)) dipole moments. The excited-state dipole moments for all the three molecules are found to be larger than their corresponding ground-state dipole moments. Further, the changes in dipole moment (Delta mu) were calculated both from solvatochromic shift method and on the basis of microscopic empirical solvent polarity parameter (E(T)(N)), and the values are compared.