- Novel synthetic coumarins that targets NF-κB in Hepatocellular carcinoma
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Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor worldwide, and is the third most common cause of cancer related death. Constitutive activation of NF-κB is the underlying mechanism behind tumorigenesis and this protein regulates the expression of genes involved in proliferation, survival, drug resistance, angiogenesis and metastasis. The design of inhibitors which suppress NF-κB activation is therefore of great therapeutic importance in the treatment of HCC. In this study, we investigated the effect of newly synthesized coumarin derivatives against HCC cells, and identified (7-Carbethoxyamino-2-oxo-2H-chromen-4-yl)methylpyrrolidine-1 carbodithioate (CPP) as lead compound. Further, we evaluated the effect of CPP on the DNA binding ability of NF-κB, CXCL12-induced cell migration and invasion, and the regulated gene products in HCC cells. We found that CPP induced cytotoxicity in three HCC cells in a time and dose dependent manner, and suppressed the DNA binding ability of NF-κB. CPP significantly decreased the CXCL12-induced cell migration and invasion. More evidently, CPP inhibits the expression of NF-κB targeted genes such as cyclin D1, Bcl-2, survivin, MMP12 and C-Myc. Furthermore, the molecular docking analysis suggested that CPP interacts with the p50 binding domain of the p65 subunit, scoring best among the 26 docked coumarin derivatives of this study. Thus, we are reporting CPP as a potent inhibitor of the pro-inflammatory pathway in Hepatocellular carcinoma.
- Neelgundmath, Mahabaleshwaraiah,Dinesh, Koragere Rajashekar,Mohan, Chakrabhavi Dhananjaya,Li, Feng,Dai, Xiaoyun,Siveen, Kodappully Sivaraman,Paricharak, Shardul,Mason, Daniel J.,Fuchs, Julian E.,Sethi, Gautam,Bender, Andreas,Rangappa, Kanchugarakoppal S.,Kotresh, Obelannavar,Basappa
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- Green approach for the synthesis of 4-coumarin-4H-pyrans from 4-formylcoumarins and their antibacterial study
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A series of 4H-pyranocoumarin derivatives have been successfully synthesized under eco-friendly condition using triethylamine as a catalyst in short reaction time with excellent yield at room temperature. All the synthesized compounds were characterized by spectral analysis and screened for their antibacterial activity against Escherichia coli and Staphylococcus aureus, the results are quite promising.
- Saxena, Alpana,Shastri, Lokesh,Sunagar, Vinay
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- Biscoumarin–pyrimidine conjugates as potent anticancer agents and binding mechanism of hit candidate with human serum albumin
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In our continuing efforts to develop therapeutically active coumarin-based compounds, a series of new C4–C4′ biscoumarin–pyrimidine conjugates (1a–l) was synthesized via SN2 reaction of substituted 4-bromomethyl coumarin with thymine. All compounds were characterized using spectroscopic techniques, that is, attenuated total reflection infrared (ATR-IR), CHN elemental analysis, and 1H and 13C NMR (nuclear magnetic resonance). In addition, the structure of compound 1d (1,3-bis[(7-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione) was established through X-ray crystallography. Compounds 1a–l were screened for in vitro anticancer activity against C6 rat glioma cells. Among the screened compounds, 1,3-bis[(6-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (1c) was identified as the best antiproliferative candidate, exhibiting an IC50 value of 4.85 μM. All the compounds (1a–l) were found to be nontoxic toward healthy human embryonic kidney cells (HEK293), indicating their selective nature. In addition, the most active compound (1c) displayed strong binding interactions with the drug carrier protein, human serum albumin, and exhibited good solution stability at biological pH conditions. Fluorescence, UV–visible spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1c with protein.
- Reddy, Dinesh S.,Kongot, Manasa,Singh, Vishal,Siddiquee, Md. Abrar,Patel, Rajan,Singhal, Nitin K.,Avecilla, Fernando,Kumar, Amit
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- Design, synthesis, molecular docking, anti-proliferative and anti-TB studies of 2H-chromen-8-azaspiro[4.5]decane-7,9-dione conjugates
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In this work, a series of new 8-[(substituted 2-oxo-2H-chromen-4-yl)methyl]-8-azaspiro[4.5]decane-7,9-dione derivatives (1a - 1l) is synthesized and characterized by 1H NMR, 13C NMR, FT-IR, GC-MS and elemental analysis. In addition, the structure of compound 1k has been elucidated using single crystal X-ray diffraction techniques. The synthesized compounds are screened for their anticancer and anti-TB activity. Preliminary anticancer results showed that compounds (1a- 1l) exhibit moderate to potent activity against MDA-MB-231, A549, HT-29 and Hela cancer cell lines. Compound 1f exhibited the most potent activity against MDA-MB-231cell line with IC50 value of 9.05 μM concentration, compound 1g and 1h showed potent activity against A549 cell line with IC50 value of 7.05 and 13.31 μM concentration respectively. Compound 1j showed good cytotoxicity against Hela cell line with IC50 of 16.14 μM, whereas, compound 1l is found to be moderately active against HT-29 cell line with IC50 of 18.07 μM. Anti-tubercular activity revealed that compound 1c, 1d, 1g, 1h and 1j have significant activity against MTBH37Rv strain with MIC 0.78, 1.56, 0.19, 0.39 and 0.78 μg/mL respectively. Further, to investigate the mechanism of anti-TB activity and detailed intermolecular interactions between the synthesized compounds, molecular docking studies are performed.
- Mane, Smita G.,Reddy, Dinesh S.,Katagi, Kariyappa S.,Kumar, Amit,Munnolli, Ravindra S.,Kadam, Nikhil S.,Akki, Mahesh C.,Nagarajaiah,Joshi, Shrinivas D.
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- Synthesis and preliminary evaluation of benzofuran-oxadiazole conjugates as potential antitubercular agents
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In the present study, a series of benzofuran-oxadiazole conjugates 7(a-o) was designed, synthesized and characterized through IR,1H NMR,13C NMR and mass spectral data. All the compounds were screened for preliminary antitubercular activity against Mycobacterium phlei and Mycobacterium tuberculosis H37RV. Among all the target compounds, the compound possessing chlorine (7k, MIC 1.56 μg/mL) and bromine (7m, MIC 1.56 μg/mL) on 6th position of benzofuran showed highest activity against Mycobacterium phlei. Whereas, bromine on either 5th position (7l, MIC 3.125 μg/mL) or 6th position (7m MIC 3.125 μg/mL) on benzofuran exhibited highest activity for Mycobacterium tuberculosis (H37 RV).
- Negalurmath, Veerabhadrayya S.,Kotresh, Obelannavar,Basanagouda, Mahantesha
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p. 965 - 970
(2019/03/07)
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- Coumarin tethered cyclic imides as efficacious glucose uptake agents and investigation of hit candidate to probe its binding mechanism with human serum albumin
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A series of novel coumarin-cyclic imide conjugates (1a–1j) were designed and synthesized to evaluate their glucose uptake activity by insulin resistant liver hepatocyte carcinoma (HepG2) cells through 2-NBDG uptake assay. Compounds (1a–1j) were characterised using various analytical methods such as 1H NMR, 13C NMR, IR, GC–MS, elemental and single-crystal X-ray diffraction techniques. Compounds (1a–1j) exhibited 85.21 – 65.80% of glucose uptake and showed low level of cytotoxicity towards human embryonic kidney cells (HEK-293) indicating good selectivity and safety profile. Compound 1f was identified as a hit candidate exhibiting 85.21% of glucose uptake which was comparable with standard antidiabetic drug Metformin (93.25% glucose uptake). Solution stability study under physiological pH conditions ≈ (3.4 – 8.7), indicates that compound 1f is sufficiently stable at varied pH conditions and thereby compatible with bio-physiological environments. Interaction of 1f with human serum albumin (HSA) were also studied which quantifies that compound 1f binds with HSA efficiently through facile binding reaction in solution. Fluorescence, UV–vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1f with protein.
- Reddy, Dinesh S.,Kongot, Manasa,Singh, Vishal,Maurya, Neha,Patel, Rajan,Kumar Singhal, Nitin,Avecilla, Fernando,Kumar, Amit
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- A click chemistry approach for the synthesis of cyclic ureido tethered coumarinyl and 1-aza coumarinyl 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis H37Rv and their in silico studies
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Nucleoside bases like uracil, pharmacophoric triazoles and benzimidazolones have been used during the present study to design molecular matrices for antitubercular activity, employing Click Chemistry. Click triazoles 4/7/10 have been obtained by the reaction of 4-(Azidomethyl)-2H-chromen-2-ones/quinolin-2(1H)-ones 3 and propargyl ethers 2/6/9 derived from theophylline/6-methyl uracil/2-benzimidazolone respectively. In addition to spectral data structures have been confirmed by single crystal X-ray diffraction studies in case of uracil bis alkyne (6) and theophylline mono triazole (4c). Theophylline linked mono triazoles, 4(a-d) and 6-methyl uracil linked bis triazoles, 7(a-e) have been found to inhibit Mycobacterium tuberculosis H37Rv with MIC values in the range 55.62–115.62 μM. Benzimidazolone bis triazoles, 10(a-n) showed better activity with MIC in the range 2.33–18.34 μM. Molecular modeling studies using Surflex-Dock algorithm supported our results.
- Khanapurmath, Netravati,Kulkarni, Manohar V.,Joshi, Shrinivas D.,Anil Kumar
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- Cu (I) Catalyzed One Pot SN-Click Reactions of Halogenated Coumarins and 1-aza-coumarins
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A one pot three component, copper catalyzed azide-alkyne cycloaddition reaction has been employed for the synthesis of bis-coumarinyl triazoles (A–D) using 4-chloro, 4-bromomethyl, 3-bromoacetyl and 4-bromomethyl-1-aza-coumarins (I–IV), sodium azide, and coumarin propargyl ethers (V–IX) in moderate yields.
- Revankar, Hrishikesh M.,Kulkarni, Manohar V.
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p. 537 - 544
(2018/01/10)
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- Synthesis of coumarin-benzotriazole hybrids and evaluation of their anti-tubercular activity
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Background: Tuberculosis is one of the top ranked airborne infectious diseases caused by the bacillus Mycobacterium tuberculosis with high mortality rate from a single infectious agent. In the present article, we aimed to synthesize oxadiazole-coumarin-triazole based small molecules and evaluate for their possible anti-mycobacterial activity. Method: Herein, we describe the facile synthesis of 5-((1H-benzo[d][1, 2, 3]triazol-1-yl)methyl)-1, 3, 4- oxadiazole-2-thiol-tethered substituted 4-(bromomethyl)-7-methyl-2H-chromen-2-one derivatives and evaluated for their anti-mycobacterial activity against H37Rv strain of M. tuberculosis. We also evaluated the cytotoxic effect of new compounds on normal cells. Results: Among the 14 novel oxadiazole-coumarin-triazole derivatives, 4-((5-((1H-benzo[d][1, 2, 3]triazol-1- yl)methyl)-1, 3, 4-oxadiazol-2-ylthio)methyl)-6-methoxy-2H-chromen-2-one (5f) displayed good antimycobacterial activity towards M. tuberculosis with an MIC value of 15.5 μM. Pyrazinamide was used as reference drug. Our investigation also revealed that, 5f is not cytotoxic to normal cells. Conclusion: In summary, the findings suggested that novel 1, 3, 4-oxadiazole coumarin-triazole hybrids are promising antimycobacterial agents against M. tuberculosis.
- Ambekar, Sachin P.,Mohan, Chakrabhavi Dhananjaya,Shirahatti, Arunkumar,Kumar, Mahesh K.,Rangappa, Shobith,Mohan, Surender,Basappa,Kotresh, Obelannavar,Rangappa, Kanchugarakoppal S.
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- Click chemistry approach for the regioselective synthesis of iso-indoline-1,3-dione-linked 1,4 and 1,5 coumarinyl 1,2,3-triazoles and their photophysical properties
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Copper-catalyzed reaction of N-propargyl isoindoline-1,3-dione and 4-azidomethyl coumarins / 4-azidomethyl-1-aza coumarins under click chemistry conditions afforded 1,4-disubstituted 1,2,3-triazoles, whereas ruthenium catalysis yielded isomeric 1,5-disubstituted 1,2,3-triazoles. The two regioisomers have been distinguished by NOE studies. UV absorption for a given pair of isomers exhibited similar trend, whereas fluorescence measurements showed considerable differences. Photo physical studies on the interaction of azides with copper and ruthenium have also been performed.
- Anand, Ashish,Kulkarni, Manohar V.
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supporting information
p. 722 - 733
(2017/03/27)
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- Cyclopropanes in water: A diastereoselective synthesis of substituted 2H-chromen-2-one and quinolin-2(1H)-one linked cyclopropanes
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A one-pot three component reaction has been developed for the synthesis of substituted cyclopropanes employing 4-bromomethyl-2H-chromen-2-one/quinolin-2(1H)-ones, aromatic aldehydes and activated nitriles. The room temperature reaction in aqueous medium has been found to be diastereoselective and high yielding.
- Anand, Ashish,Yenagi, Jayashree,Tonannavar,Kulkarni, Manohar V.
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supporting information
p. 2201 - 2205
(2016/04/19)
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- Efficient and Convenient Method for Synthesis of Benzofuran-3-acetic Acids and Naphthafuran-acetic Acids
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Herein, we report an efficient and convenient method for synthesis of benzofuran-3-acetic acids and naphthafuran-acetic acids 5a-p by the reaction of substituted-4-bromomethylcoumarins with aqueous sodium hydroxide at refluxing temperature. The obtained products are characterized by infrared, 1H NMR, 13C NMR, and mass spectral data. Structures 5a and 5e are confirmed by their single x-ray diffraction studies. The advantages of this method are good yields, easy workup, and no chromatographic purifications.
- Basanagouda, Mahantesha,Narayanachar,Majati, Iranna B.,Mulimani, Shiddappa S.,Sunnal, Satish B.,Nadiger, Rohit V.,Ghanti, Ashok S.,Gudageri, Siddeshwar F.,Naik, Ravi,Nayak, Akshata
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p. 2195 - 2202
(2015/09/22)
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- A click chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl triazoles as anti-tubercular agents
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A series of mono and bis-triazole coumarin hybrids 6aeu and 9aef respectively have been synthesized using 4-(azidomethyl)-2H-chromen-2-ones 5aei and aryl propargyl ethers 2aec/8 employing Click chemistry modified protocol for Azide-Alkyne cycloadditions(CuAAC). Anti-tubercular screening showed moderate activity for mono aryloxy compounds 6aeu with MIC 50-100 μg/mL, whereas the bis compounds 9aef were more effective with MICs between 0.2 and 12.5 μg/mL. Molecular modeling and 3DQSAR 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.
- Anand, Ashish,Naik, Reshma J.,Revankar, Hrishikesh M.,Kulkarni, Manohar V.,Dixit, Sheshagiri R.,Joshi, Shrinivas D.
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p. 194 - 207
(2015/11/03)
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- A facile synthesis and evaluation of new biomolecule-based coumarin-thiazoline hybrids as potent anti-tubercular agents with cytotoxicity, DNA cleavage and X-ray studies
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An efficient and rapid synthesis of coumarin-thiazoline hybrids (1a-1j) under microwave irradiation is described with high yields. The synthesized compounds were characterized using elemental and spectroscopic analysis; in addition, the structures of compounds 1a, 1b, 1e and 1h have been elucidated using single crystal X-ray diffraction techniques. All the newly synthesized compounds were screened for their in vitro anti-tubercular activity and in a DNA cleavage study, while the most active compounds were subjected to a cytotoxicity assay on Vero cell lines. Among those tested, compound 1b exhibited excellent anti-tubercular activity (MIC 0.09 μg ml-1) with a low level of cytotoxicity, suggesting that compound 1b is a promising lead for subsequent investigations in search of new anti-tubercular agents. Furthermore, a DNA cleavage study using an agarose gel electrophoresis method revealed that compounds 1b, 1d, 1f and 1i cleaved DNA more efficiently and thereby exhibit nuclease activity.
- Reddy, Dinesh S.,Hosamani, Kallappa M.,Devarajegowda, Hirihalli C.,Kurjogi, Mahantesh M.
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p. 64566 - 64581
(2015/08/18)
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- Synthesis, structure-activity relationship of iodinated-4-aryloxymethyl- coumarins as potential anti-cancer and anti-mycobacterial agents
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A series of new iodinated-4-aryloxymethylcoumarins 6, 8 and 10 have been obtained from the reaction of various 4-bromomethylcoumarins 4 with 2-iodophenol 5, 3-iodophenol 7 and 4-iodophenol 9 respectively. All the title compounds were screened for anticancer activity against two cancer cell lines (MDA-MB human adenocarcinoma mammary gland and A-549 human lung carcinoma) and two mycobacterial strains (Mycobacterium tuberculosis H37 RV and Mycobacterium phlei). The SAR results indicate that nine compounds are potent, among these 10h and 10i having chlorine are most effective. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of iodinated-4-aryloxymethyl-coumarins.
- Basanagouda, Mahantesha,Jambagi, Vishwanath B.,Barigidad, Nivedita N.,Laxmeshwar, Sandeep S.,Devaru, Venkatesh,Narayanachar
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p. 225 - 233
(2014/02/14)
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- Synthesis, biological evaluation and docking studies of 4-aryloxymethyl coumarins derived from substructures and degradation products of vancomycin
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Two series of 4-aryloxymethyl coumarins derived from the reaction of 4-bromomethyl coumarins with ethyl gallate and ethyl ester of N-Benzoyl tyrosine have been synthesized. Gallate ethers 3a-3g and tyrosine derivatives 4e-4j were most effective against Entercoccusfaecalis. They were also found to be effective against Aspergillusniger and Candidaalbicans. Comparative docking studies with novobiocin have indicated better binding ability and higher 'C' score values than novobiocin.
- Revankar, Hrishikesh M.,Kulkarni, Manohar V.,Joshi, Shrinivas D.,More, Uttam A.
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p. 750 - 757
(2013/12/04)
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- Click Chemistry Approach for Bis-Chromenyl Triazole Hybrids and Their Antitubercular Activity
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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 6.25μg/mL MIC against M. tuberculosis. Among the compounds screened for antifungal activity, lowest MIC of 6.25μg/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.
- Naik, Reshma J.,Kulkarni, Manohar V.,Sreedhara Ranganath Pai,Nayak, Pawan G.
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p. 516 - 523
(2012/11/07)
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- Synthesis and in vitro antitubercular activity of 4-aryl/ alkylsulfonylmethylcoumarins as inhibitors of Mycobacterium tuberculosis
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A series of 4-aryl/alkylsulfonylmethylcoumarins have been synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (MTB). Four of the compounds showed MIC in the range of 0.78-3.13 μg/mL proving their potential activity.
- Jeyachandran, Malaichamy,Ramesh, Penugonda,Sriram, Dharmarajan,Senthilkumar, Palaniappan,Yogeeswari, Perumal
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supporting information; experimental part
p. 4807 - 4809
(2012/08/07)
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- Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents
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The naturally occurring coumarins and resveratrol, attract great attention due to their wide range of biological properties, including anticancer, antileukemic, antibacterial and anti-inflammatory activities; moreover, their cancer chemopreventive property have been recently emphasized. A novel class of hybrid compounds, obtained by introducing a substituted trans-vinylbenzene moiety on a coumarin backbone, was synthesized and evaluated for the antitumor profile. A number of derivatives showed a good antiproliferative activity, in some cases higher to that of the reference compound resveratrol. The most promising compounds in this series were 14 and 17, endowed with excellent antiproliferative and proapoptotic activities. The present study suggests that the 7-methoxycoumarin nucleus, together with the 3,5-disubstitution pattern of the trans-vinylbenzene moiety, are likely promising structural features to obtain excellent antitumor compounds endowed with a apoptosis-inducing capability.
- Belluti, Federica,Fontana, Gabriele,Bo, Laura Dal,Carenini, Nives,Giommarelli, Chiara,Zunino, Franco
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experimental part
p. 3543 - 3550
(2010/07/17)
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- Synthesis, antibacterial and analgesic evaluation of S-(2-oxo-2H-chromen-4- ylmethyl) thiocarbamates
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Bromination of 7-methoxy-4-methyl-2H-chromen-2-one 1 afforded 7-methoxy-4-bromomethyl-2H-chromen-2-one 2, which on further reaction with potassium thiocyanate gave 7-methoxy-4-(thiocyanatomethyl)-2H-chromen-2-one 3, treatment of 3 with appropriate alcohols in the presence sulphuric acid yielded corresponding thiocarbamates 4a-e. These were screened for antibacterial and analgesic properties.
- Jeyachandran,Ramesh
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scheme or table
p. 233 - 236
(2011/12/14)
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- Reaction of 4-Haloacetoacetate with Phenols in the Presence of Aluminium Chloride
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Reaction of ethyl 4-bromoacetoacetate (1) with phenol in the presence of aluminium chloride gave ethyl 4-bromo-3-hydroxy-3-(2-hydroxyphenyl)butyrate (3a), which can be regarded as an intermediate of the Pechmann reaction.Similar reaction of ethyl 4-chloroacetoacetate (7) with phenol in the presence of aluminium chloride gave the 4-chloro derivative 8a.Compound 3a was treated with either hydrogen chloride in ethanol or triethylamine followed by treatment with p-toluenesulfonic acid to give 4-bromomethylcoumarin (4a) or ethyl 3-benzofuranacetate (6a), respectively.Similarly, reactions of phenol derivatives 2 with 1 gave the corresponding 3-hydroxybutyrates 3, which were transformed to the coumarins 4 and the 3-benzofuranacetates 6.
- Kimura, Hitoshi,Sato, Hirotoshi,Tsuchiya, Chizuko,Chiba, Takuo,Kato, Tetsuzo
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p. 552 - 558
(2007/10/02)
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