Browsing by Author "Sriram, D."

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Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition
(2013) Panathur, N.; Udayakumar, D.; Koushik, P.V.; Alvala, M.; Yogeeswari, P.; Sriram, D.; Kumar, V.
In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3- yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. 2013 Elsevier Masson SAS. All rights reserved.
Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition
(2013) Panathur, N.; Udayakumar, U.; Koushik, P.V.; Alvala, M.; Yogeeswari, P.; Sriram, D.; Kumar, V.
In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3- yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. © 2013 Elsevier Masson SAS. All rights reserved.
Ionic liquid-promoted one-pot synthesis of thiazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids and their antitubercular activity
(2016) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
In this paper, we report the facile and efficient one-pot three-component synthesis of 1-((6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-2-(4-phenylthiazol-2-yl)hydrazine derivatives (5a-w) using an ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([Bmim]Br). The compounds were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. Compound 5s showed the highest inhibitory activity with an MIC of 6.03 ?M which is slightly lower than the MIC values of standard drugs ethambutol (15.3 ?M) and ciprofloxacin (9.4 ?M). Four other compounds of the series viz.5e, 5i, 5t and 5w also showed significant inhibitory activity with MIC values in the range of 11.7-13.9 ?M. The structure-activity relationship revealed that the trifluoromethyl substitution at position-2 and p-chlorophenyl substitution at position-6 of the imidazo[2,1-b][1,3,4]thiadiazole ring enhanced the inhibitory activity. Also, the methyl, methoxy, fluoro or nitro substituents on the thiazole ring enhanced the activity of the compounds. None of the active compounds were toxic to a normal cell line (NIH 3T3), which signifies the lack of general cellular toxicity of the molecules. In silico molecular docking studies revealed the favourable interaction of the potent compounds with the target enzymes InhA and CYP121. The Royal Society of Chemistry 2016.
Ionic liquid-promoted one-pot synthesis of thiazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids and their antitubercular activity
(Royal Society of Chemistry, 2016) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
In this paper, we report the facile and efficient one-pot three-component synthesis of 1-((6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-2-(4-phenylthiazol-2-yl)hydrazine derivatives (5a-w) using an ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([Bmim]Br). The compounds were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. Compound 5s showed the highest inhibitory activity with an MIC of 6.03 ?M which is slightly lower than the MIC values of standard drugs ethambutol (15.3 ?M) and ciprofloxacin (9.4 ?M). Four other compounds of the series viz.5e, 5i, 5t and 5w also showed significant inhibitory activity with MIC values in the range of 11.7-13.9 ?M. The structure-activity relationship revealed that the trifluoromethyl substitution at position-2 and p-chlorophenyl substitution at position-6 of the imidazo[2,1-b][1,3,4]thiadiazole ring enhanced the inhibitory activity. Also, the methyl, methoxy, fluoro or nitro substituents on the thiazole ring enhanced the activity of the compounds. None of the active compounds were toxic to a normal cell line (NIH 3T3), which signifies the lack of general cellular toxicity of the molecules. In silico molecular docking studies revealed the favourable interaction of the potent compounds with the target enzymes InhA and CYP121. © The Royal Society of Chemistry 2016.
New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies
(2015) Panathur, N.; Gokhale, N.; Udayakumar, D.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.
A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 ?M, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme. 2015 Elsevier Ltd. All rights reserved.
New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies
(Elsevier Ltd, 2015) Panathur, N.; Gokhale, N.; Udayakumar, U.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.
A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 ?M, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme. © 2015 Elsevier Ltd. All rights reserved.
One-pot synthesis of new triazole - Imidazo[2,1-b][1,3,4]thiadiazole hybrids via click chemistry and evaluation of their antitubercular activity
(2015) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
A new series of triazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a-s, 7a) were designed by a molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry protocol. All the intermediates and final molecules were characterised using spectral methods and one of the target compounds (6c) was analysed by the single crystal XRD study. The derivatives were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 6f and 6n, demonstrated significant growth inhibitory activity against the bacterial strain with a MIC of 3.125 ?g/mL. The presence of chloro substituent on the imidazo[2,1-b][1,3,4]thiadiazole ring and ethyl, benzyl or cyanomethylene groups on the 1,2,3-triazole ring enhance the inhibition activity of the molecules. The active compounds are not toxic to a normal cell line which signifies the lack of general cellular toxicity of these compounds. 2015 Elsevier Ltd. All rights reserved.
One-pot synthesis of new triazole - Imidazo[2,1-b][1,3,4]thiadiazole hybrids via click chemistry and evaluation of their antitubercular activity
(Elsevier Ltd, 2015) Ramprasad, J.; Nayak, N.; Udayakumar, U.; Yogeeswari, P.; Sriram, D.
A new series of triazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids (6a-s, 7a) were designed by a molecular hybridisation approach and the target molecules were synthesized via one pot click chemistry protocol. All the intermediates and final molecules were characterised using spectral methods and one of the target compounds (6c) was analysed by the single crystal XRD study. The derivatives were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 6f and 6n, demonstrated significant growth inhibitory activity against the bacterial strain with a MIC of 3.125 ?g/mL. The presence of chloro substituent on the imidazo[2,1-b][1,3,4]thiadiazole ring and ethyl, benzyl or cyanomethylene groups on the 1,2,3-triazole ring enhance the inhibition activity of the molecules. The active compounds are not toxic to a normal cell line which signifies the lack of general cellular toxicity of these compounds. © 2015 Elsevier Ltd. All rights reserved.
Synthesis and antimycobacterial screening of new N-(4-(5-aryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)-4-amide derivatives
(2016) Nayak, N.; Ramprasad, J.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
This article demonstrates the synthesis, characterization and the study of in vitro antitubercular activities of twenty four new N-(4-(5-aryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)-4-amide derivatives (8a-x). The antitubercular activity of the compounds against Mycobacterium tuberculosis H37Rv (MTB) revealed that 2-chloro-N-(4-(5-(4-chlorophenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)benzamide (8n) is the most promising lead molecule with a MIC of 1.56 ?g/mL, while the corresponding unsubstituted benzamide derivative (8o) is the next most active molecule with a MIC of 3.13 ?g/mL. Interestingly, the pyrazole intermediate 5b containing chlorophenyl and N-acylcarbohydrazide substituents also showed significant activity (MIC = 3.13 ?g/mL). Further, the active molecules did not show toxicity against a normal NIH 3T3 cell line, signifying their suitability for further drug development. 2016 Udayakumar Dalimba.
Synthesis and antimycobacterial screening of new N-(4-(5-aryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)-4-amide derivatives
(Elsevier, 2016) Nayak, N.; Ramprasad, J.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
This article demonstrates the synthesis, characterization and the study of in vitro antitubercular activities of twenty four new N-(4-(5-aryl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)-4-amide derivatives (8a-x). The antitubercular activity of the compounds against Mycobacterium tuberculosis H37Rv (MTB) revealed that 2-chloro-N-(4-(5-(4-chlorophenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)phenyl)benzamide (8n) is the most promising lead molecule with a MIC of 1.56 ?g/mL, while the corresponding unsubstituted benzamide derivative (8o) is the next most active molecule with a MIC of 3.13 ?g/mL. Interestingly, the pyrazole intermediate 5b containing chlorophenyl and N-acylcarbohydrazide substituents also showed significant activity (MIC = 3.13 ?g/mL). Further, the active molecules did not show toxicity against a normal NIH 3T3 cell line, signifying their suitability for further drug development. © 2016 Udayakumar Dalimba.
Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole-benzimidazole derivatives
(2015) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.; Peethambar, S.K.; Achur, R.; Kumar, H.S.S.
In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by 1H NMR, 13C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 ?g/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line. 2015 Elsevier Masson SAS.
Synthesis and biological evaluation of new imidazo[2,1-b][1,3,4]thiadiazole-benzimidazole derivatives
(Elsevier Masson SAS infos@masson.fr 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442, 2015) Ramprasad, J.; Nayak, N.; Udayakumar, U.; Yogeeswari, P.; Sriram, D.; Peethambar, S.K.; Achur, R.; Santosh Kumar, H.S.S.
In this report, we describe the synthesis and biological evaluation of a new series of 2-(imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-1H-benzimidazole derivatives (5a-ac). The molecules were analyzed by 1H NMR, 13C NMR, mass spectral and elemental data. The structure of one of the pre-final compounds, 6-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d) and that of a target compound, 2-[2-methyl-6-(4-methyl phenyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzimidazole (5aa) were confirmed by single crystal XRD studies. All the target compounds were screened for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Seven (5c, 5d, 5l, 5p, 5r, 5z and 5aa) out of twenty nine compounds showed potent anti-tubercular activity with a MIC of 3.125 ?g/mL. A p-substituted phenyl group (p-tolyl or p-chlorophenyl) in the imidazo[2,1-b][1,3,4]thiadiazole ring and/or a chloro group in the benzimidazole ring enhance anti-tuberculosis activity whereas a nitro group in the benzimidazole ring reduces the activity. In the antibacterial screening, compounds 5i, 5w and 5ac showed promising activity against the tested bacterial strains. Further, antifungal and antioxidant activities of these molecules were also investigated. In the cytotoxicity study, the active antitubercular compounds exhibited very low toxicity against a normal cell line. © 2015 Elsevier Masson SAS.
Synthesis of new pyrazole-triazole hybrids by click reaction using a green solvent and evaluation of their antitubercular and antibacterial activity
(2016) Nayak, N.; Ramprasad, J.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.; Kumar, H.S.S.; Peethambar, S.K.; Achur, R.
A new series of pyrazole-based 1,2,3-triazole derivatives (6a-x) were synthesized by employing click reaction using a 2:1 mixture of PEG-400 and water as green solvent. The synthesized intermediate and final compounds were characterized by 1H NMR, 13C NMR, and mass spectra and elemental analysis techniques. The structure of one of the final compounds, 6a was evidenced by single crystal X-ray diffraction study. Among the twenty-four compounds, five compounds (6a, 6b, 6d, 6f, and 6g) showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv with a minimum inhibitory concentration (MIC) ? 6.25 ?g/mL. The 4-(((5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)methoxy)methyl)-1-cyclohexyl-1H-1,2,3-triazole (6g) was the most potent compound of the series, which showed a MIC of 3.13 ?g/mL. The cytotoxicity study of active anti-TB compounds on normal Vero cells revealed that the compounds are non-toxic with a high selectivity index (>37). Most of the pyrazole-1,2,3-triazole derivatives with a 4-chlorophenyl substitution at position-5 of the pyrazole ring showed a better anti-TB activity than the corresponding 4-bromophenyl or 4-methoxyphenyl substituted derivatives. The target compounds were also evaluated for their in vitro antibacterial activity and six compounds (6a, 6c, 6d, 6e, 6l, and 6w) showed promising inhibition activity against four tested strains. Springer Science+Business Media Dordrecht 2015.
Synthesis of new pyrazole-triazole hybrids by click reaction using a green solvent and evaluation of their antitubercular and antibacterial activity
(Springer Netherlands, 2016) Nayak, N.; Ramprasad, J.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.; Santosh Kumar, H.S.S.; Peethambar, S.K.; Achur, R.
A new series of pyrazole-based 1,2,3-triazole derivatives (6a-x) were synthesized by employing click reaction using a 2:1 mixture of PEG-400 and water as green solvent. The synthesized intermediate and final compounds were characterized by 1H NMR, 13C NMR, and mass spectra and elemental analysis techniques. The structure of one of the final compounds, 6a was evidenced by single crystal X-ray diffraction study. Among the twenty-four compounds, five compounds (6a, 6b, 6d, 6f, and 6g) showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv with a minimum inhibitory concentration (MIC) ? 6.25 ?g/mL. The 4-(((5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)methoxy)methyl)-1-cyclohexyl-1H-1,2,3-triazole (6g) was the most potent compound of the series, which showed a MIC of 3.13 ?g/mL. The cytotoxicity study of active anti-TB compounds on normal Vero cells revealed that the compounds are non-toxic with a high selectivity index (>37). Most of the pyrazole-1,2,3-triazole derivatives with a 4-chlorophenyl substitution at position-5 of the pyrazole ring showed a better anti-TB activity than the corresponding 4-bromophenyl or 4-methoxyphenyl substituted derivatives. The target compounds were also evaluated for their in vitro antibacterial activity and six compounds (6a, 6c, 6d, 6e, 6l, and 6w) showed promising inhibition activity against four tested strains. © Springer Science+Business Media Dordrecht 2015.
Synthesis of novel 5-[(1,2,3-triazol-4-yl)methyl]-1-methyl-3H-pyridazino[4,5-b]indol-4-one derivatives by click reaction and exploration of their anticancer activity
(2016) Panathur, N.; Gokhale, N.; Udayakumar, D.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.
A series of pyridazino[4,5-b]indole derivatives containing alkyl-, benzyl- and phenacyl-substituted 1,2,3-triazolylmethyl units was synthesized using click chemistry approach. All 30 compounds of the series were screened in vitro against four cancer cell lines, viz. breast cancer cells MDA-MB-231 and MCF 7, human primary glioblastoma U-87 and human neuroblastoma IMR-32 cell lines. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. The IC50 value of compounds 7v and 7x against human neuroblastoma IMR-32 cell line is 0.07 and 0.04 ?M, respectively. Among the tested compounds, ten compounds showed IC50 value less than 1 ?M against MDA-MB-231 cells, whereas against IMR-32 cells, nine compounds and, against U-87 cells, six compounds showed similar inhibition activity. Further, these molecules exhibited prominent binding affinity and docking scores in the molecular simulation study with the target enzyme PI3 kinase. Graphical Abstract: This paper illustrates the synthesis of new fused indole-pyridazinone derivatives containing substituted 1,2,3-triazoles via click chemistry approach. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. [Figure not available: see fulltext.] 2015 Springer Science+Business Media New York.
Synthesis of novel 5-[(1,2,3-triazol-4-yl)methyl]-1-methyl-3H-pyridazino[4,5-b]indol-4-one derivatives by click reaction and exploration of their anticancer activity
(Birkhauser Boston, 2016) Panathur, N.; Gokhale, N.; Udayakumar, U.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.
A series of pyridazino[4,5-b]indole derivatives containing alkyl-, benzyl- and phenacyl-substituted 1,2,3-triazolylmethyl units was synthesized using click chemistry approach. All 30 compounds of the series were screened in vitro against four cancer cell lines, viz. breast cancer cells MDA-MB-231 and MCF 7, human primary glioblastoma U-87 and human neuroblastoma IMR-32 cell lines. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. The IC50 value of compounds 7v and 7x against human neuroblastoma IMR-32 cell line is 0.07 and 0.04 ?M, respectively. Among the tested compounds, ten compounds showed IC50 value less than 1 ?M against MDA-MB-231 cells, whereas against IMR-32 cells, nine compounds and, against U-87 cells, six compounds showed similar inhibition activity. Further, these molecules exhibited prominent binding affinity and docking scores in the molecular simulation study with the target enzyme PI3 kinase. Graphical Abstract: This paper illustrates the synthesis of new fused indole-pyridazinone derivatives containing substituted 1,2,3-triazoles via click chemistry approach. Most of the compounds exhibited potent cancer cell growth inhibition activity at very low micromolar concentrations. [Figure not available: see fulltext.] © 2015 Springer Science+Business Media New York.