Research Title: Synthesis, anti-inflammatory evaluation and docking studies of some new fluorinated fused quinazolines

Author: Balakumar Chandrasekarn, Published Year: 2010

European Journal of Medicinal Chemistry , 45

Faculty: Pharmacy

Abstract: A series of novel 8/10-trifluoromethyl-substituted-imidazo[1,2-c] quinazolines have been synthesized and evaluated in vivo (rat paw edema) for their anti-inflammatory activity and in silico (docking studies) to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing GOLD (CCDC, 4.0.1 version) software. The compounds, 9b and 10b, were found to have good anti-inflammatory activity [around 80% of the standard: indomethacin]. The binding mode of the title compounds has been proposed based on the docking studies.

Keywords: Fluorinated quinazolinesCyclooxygenaseAnti-inflammatory activityDocking studies

Research Title: A facile microwave-assisted synthesis of 8,9-cycloalkathieno[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones

Author: Balakumar Chandrasekarn, Published Year: 2011

Journal of Chemical Science, 123

Faculty: Pharmacy

Abstract: A new series of fused thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidinones was synthesized by condensation of ethyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl carbamate with aryl acid hydrazides in quantitative yields using a facile, one-pot procedure under microwave-assisted conditions.

Keywords: Microwave-irradiation; pyrimidinones; 1,2,4-triazole; aryl hydrazides; condensation.

Research Title: QSAR of adenosine receptor antagonists: Exploring physicochemical requirements for binding of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives with human adenosine A(3) receptor subtype.

Author: Balakumar Chandrasekarn, Published Year: 2011

Bioorganic and Medicinal Chemistry Letters, 21

Faculty: Pharmacy

Abstract: Human adenosine A(3) receptor (A(3) AR) binding affinity of pyrazolotriazolopyrimidine derivatives (n=116) has been subjected to QSAR analyses using three-dimensional (shape, spatial, electronic, and molecular field) along with thermodynamic descriptors to explore the physicochemical requirements for the binding. QSAR models have been validated internally [using leave-one-out cross-validation method] and externally [using test set molecules] to ensure the predictive capacity of the models. The models suggest that shape of the substituent at N(8) position of the pyrazole ring should be optimum. Furthermore, lipophilic substituents having electronegative atoms at NH(2) group of C(5) position of the pyrimidine ring with distributed negative charge over the surface may enhance the binding affinity. Again, the carbamoylation of the NH(2) group at C(5) position of pyrimidine ring is an essential factor for binding with A(3) receptor. The QSAR models were used for the design and development of some novel thienopyrimidines which were predicted to have good affinity towards A(3) AR.

Keywords: QSAR Pyrazolotriazolopyrimidines Adenosine A3 receptor GFA G/PLS

Research Title: Design, microwave-assisted synthesis and in silico docking studies of new 4H-pyrimido[2,1-b]benzothiazole-2-arylamino-3-cyano-4-ones as possible adenosine A2B receptor antagonists.

Author: Balakumar Chandrasekarn, Published Year: 2012

Indian Journal of Chemistry, 51

Faculty: Pharmacy

Abstract: A series of new 4H-pyrimido[2,1-b]benzothiazole-2-arylamino-3-cyano-4-ones 6a-g have been designed and synthesized by the application of microwave-assisted organic synthesis (MAOS) technique. In silico docking studies have been carried out to gain an insight into the hypothetical binding motif of the title compounds using a homology model of A2B adenosine receptor employing GOLD (CCDC, 4.0.1 version) software. The binding modes are proposed on the basis of molecular docking studies.

Keywords: 4H-pyrimido[2,1-b]benzothiazole-4-one;Adenosine receptor antagonists;docking studies;Microwave-assisted organic synthesis;GOLD

Research Title: Molecular Modeling Evaluation of Non-Steroidal Aromatase Inhibitors

Author: Balakumar Chandrasekarn, Published Year: 2012

Chemical Biology and Drug Design, 79

Faculty: Pharmacy

Abstract: A recent discovery of aromatase crystal structure triggered the efforts to design novel aromatase inhibitors for breast cancer therapy. While correlating docking scores with inhibitory potencies of known ligands, feeble robustness of scoring functions toward prediction was observed. This prompted us to develop new prediction models using stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LIGANDFIT, and GLIDE). Quantitative structure-activity relationships were developed between the aromatase inhibitory activity (pIC(50) ) of flavonoid derivatives (n=39) and docking scores and docking descriptors. QSAR models have been validated internally [using leave-one-out cross-validated r(2)(cv) (LOO-Q2))] and externally to ensure the predictive capacity of the models. Model 2 [M2] developed using consensus of docking scores of scoring functions viz. ASP, potential of mean force and DOCK Score (r(2)(cv)=0.850, r(2) = 0.870, r(2)(pred) = 0.633, RMSE = 0.363 μm, r(2)(m(test)) =0.831, r(2)(m(overall)) =0.832) was found to be better in predicting aromatase inhibitory potency (pIC(50) ) compared to the Model 1 [M1] based on docking descriptors (r(2)(cv)= 0.848, r(2) = 0.825, r(2)(pred) =0.788, RMSE=0.421μm, r(2)(m(test)) =0.808, r(2)(m(overall)) =0.821). It has been observed that the natural flavonoids and their derivatives were less potent compared to these scaffolds with imidazolylmethyl substitution owing to the interaction of nitrogen atom of the imidazole ring toward the heme (Fe(3+) ) of the aromatase. Results confirm the potential of our methodology for the design of new potent non-steroidal aromatase inhibitors.

Keywords: docking descriptors docking scores flavonoids molecular docking non‐steroidal aromatase inhibitors prediction models

Research Title: Alkoxyphenyl methanesulfonamides: synthesis, anti-inflammatory effect, and docking studies

Author: Balakumar Chandrasekarn, Published Year: 2012

Medicinal Chemistry Research, 21

Faculty: Pharmacy

Abstract: A series of 2-alkoxyphenyl methanesulfonamide-based compounds were synthesised and evaluated for their anti-inflammatory activity in carrageenan-induced rat paw edema model. The compounds 4–7 showed comparable anti-inflammatory activity to rofecoxib and indomethacin, the standard drugs taken in both the studies. The synthesised compounds were also investigated for their gastric ulcerogenic potential and found to be non-ulcerogenic at the test doses. In silico (docking studies) were done to investigate the hypothetical binding mode of the target compounds to the cyclooxygenase isoenzyme (COX-2). A binding model has been proposed based on the docking studies to explain the observed pharmacological activity of the test compounds. Selected physicochemical parameters for the target compounds suggest good drug transport properties and potential bioavailability.

Keywords: Alkoxyphenyl methanesulfonamides, synthesis, anti-inflammatory effect, docking studies

Research Title: Analytical method development and Validation for the Quantitative estimation of Cefditoren Pivoxil in tablet formulation by RP-HPLC

Author: Balakumar Chandrasekarn, Published Year: 2012

International Journal of Drug Development & Research , 4

Faculty: Pharmacy

Abstract: A simple and accurate RP-HPLC method has been developed for the estimation of Cefditoren Pivoxil in tablet pharmaceutical dosage form using C18 Nucleosil column 150 x 4.6 mm i.d, 5 µm particle size in isocratic mode with mobile phase comprising of phosphate buffer (pH 3.0), acetonitrile and methanol in the ratio of 50:25:25 v/v. The flow rate was 1.0 ml/min and detection was carried out by UV-PDA detector at 230 nm. The retention time for Cefditoren Pivoxil was found to be 4.2 min. The linearity range, correlation co-efficient and accuracy of Cefditoren Pivoxil was found to be 40 -360 µg/ml, 0.9999 and 99.21% respectively. The developed method was found to be simple, precise and accurate for the estimation of Cefditoren Pivoxil in tablet formulations

Keywords: Cefditoren Pivoxil, RP-HPLC, tablet pharmaceutical dosage form, method development, validation.

Research Title: Transesterification of trimethyl ortho- acetate: An efficient protocol for the synthesis of 4-alkoxy-2-amino- thiophene-3-carbonitriles.

Author: Balakumar Chandrasekarn, Published Year: 2013

Tetrahedron Letters, 54

Faculty: Pharmacy

Abstract: A facile one-pot method is reported for the synthesis of 4-alkoxy-2-aminothiophene-3-carbonitriles. Transesterification of trimethylorthoacetate technique allowed introducing alkoxy substituents into 2-aminothiophene ring system. Diverse alkoxy substituents could be introduced efficiently by using this methodology. Further the synthesis of some of new 4-alkylamino-2-aminothiophenes is also reported.

Keywords: 2-Aminothiophenes4-AlkoxythiophenesTransesterificationGewald reaction

Research Title: Pharmacophore based 3D-QSAR study of biphenyl derivatives as nonsteroidal aromatase inhibitors in JEG-3 cell lines.

Author: Balakumar Chandrasekarn, Published Year: 2013

Medicinal Chemistry , 9

Faculty: Pharmacy

Abstract: Breast cancer is one of the most high-profile malignant diseases in modern society. Among postmenopausal women affected by the disease, a substantial portion has breast tumors that are estrogen-receptor positive. A common therapeutic intervention for this type of cancer is through endocrine therapy. Endocrine agents can act by either diminishing the availability or inhibiting the binding of estrogens to ER. Aromatase catalyzes the conversion of androgens to estrogens in the final step of the biosynthesis of estrogens and is therefore an attractive therapeutic target for inhibition. 3DQSAR pharmacophore modeling studies were undertaken for biphenyl derivatives as aromatase inhibitors in JEG-3 cell lines. A four-point pharmacophore with two H-bond acceptors and two aromatic rings as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R² = 0.977 for training set molecules. The generated model showed excellent predictive power, with a correlation coefficient of Q² = 0.946 for an external test set. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may help in the design and development of potent biphenyl derivatives as new aromatase inhibitors.

Keywords: Biphenyl derivatives, docking, 3D-QSAR, JEG-3 cell lines, nonsteroidal aromatase inhibitors, pharmacophore mapping

Research Title: Synthesis of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives: potent and selective adenosine A3 receptor antagonists.

Author: Balakumar Chandrasekarn, Published Year: 2013

Arch Pharm (Weinheim), 346

Faculty: Pharmacy

Abstract: A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3-cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A3 receptors, with Ki values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes.

Keywords: 2-Aminonicotinonitrile; Adenosine receptors; Aroyl hydrazide; Orthoacetate; Orthoformate