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

Research Title: Synthesis, anti-inflammatory evaluation, and docking studies of some new thiazole derivatives

Author: Balakumar Chandrasekarn, Published Year: 2014

Medicinal Chemistry Research, 23

Faculty: Pharmacy

Abstract: A series of new 2-substituted-N-(1,3-thiazole-2-yl)acetamide 3–7 and N-(benzo[d]thiazol-2-yl)-2-(substituted)acetamide 10–13 derivatives have been synthesized and evaluated in vivo (rat paw edema) for their anti-inflammatory activities and in silico(docking studies) to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzyme (COX-2) employing GLIDE software (Schrodinger Inc.). The compounds, 10–13 were found to have good anti-inflammatory activities [around 84–93 % of the standard: indomethacin]. The binding mode of the title compounds has been proposed based on the docking studies. Further, the predicted ADME properties of all the tested compounds were found to be in the ranges as predicted by QikProp for 95 % of known oral drugs and also satisfy the Lipinski’s rule of five.

Keywords: anti-inflammatory evaluation, docking studies

Research Title: Development and Validation of a Specific RP-HPLC Method for the Estimation of γ-Aminobutyric Acid in Rat Brain Tissue Samples Using Benzoyl Chloride Derivatization and PDA Detection

Author: Balakumar Chandrasekarn, Published Year: 2015

Acta Chromatographica, 27

Faculty: Pharmacy

Abstract: A new, rapid, and specific reversed phase high-performance liquid chromatographic (RP-HPLC) method involving precolumn derivatization with benzoyl chloride was developed and validated for the estimation of γ-aminobutyric acid (GABA) in rat brain tissue preparations. The derivatization product of GABA was identified by melting point, infrared, and proton nuclear magnetic resonance (1H NMR) spectroscopy to be n-benzoyl GABA. Various parameters which influenced derivatization and elusion were optimized. The chromatographic system consisted of C-18 column with ultraviolet (UV)—photodiode array detection ranging from 210 to 400 nm. Elution with an isocratic mobile phase consisting of 0.025 M disodium hydrogen phosphate buffer—methanol (65:35, v/v; pH 6) at a flow rate of 1 mL min−1 yielded sharp and specific peak of n-benzoyl GABA within 7 min. The method was validated with respect to the linearity, accuracy, precision, sensitivity, selectivity, and stability, wherein the benzoyl derivative of GABA showed stability for 2 months. The lower limit of detection was 0.5 nmol L−1. This novel derivatization procedure for the estimation of GABA with benzoyl chloride was also applied for rat brain tissue preparations that gave highly specific peak and good component recovery. The results show that the method for the determination of GABA by benzoylation using RP-HPLC has good linearity, accuracy, precision, sensitivity, and specificity and is simple and economical to perform.

Keywords: GABA, benzoyl chloride, RP-HPLC, PDA, brain tissues, validation

Research Title: Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents

Author: Balakumar Chandrasekarn, Published Year: 2016

ACS Medicinal Chemistry Letters, 7

Faculty: Pharmacy

Abstract: Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.

Keywords: Antimycobacterial activity bactericidal dehydrozingerone NIAID thiazole

Research Title: Whole exome sequencing highlights variants in association with Keratoconus in Jordanian families

Author: Tawfiq Froukh, Published Year: 2019

BMC Medical Genetics,

Faculty: Science

Abstract: Background Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical, resulting in myopia, irregular astigmatism, and corneal scarring. Methods eight families characterized by multiple keratoconic individuals and consanguineous marriages were examined genetically. Whole exome sequencing was done as trio or quadro per family. The filtration procedure based on minor allele frequency (MAF) less than 0.01 for homozygous variants and MAF=0 for heterozygous variants identified twenty-two missense variants. Candidate variants were prioritized based on the protein function and six variants were highlighted in five families. Results Two variants were highlighted in one family within the genes MYOF and STX2, and one variant is highlighted in each of the other four families within the genes: MLLT4, COL6A5, ZNF676 and ZNF765. Conclusion This study is one of the very rare that highlights genetic variants in association with KC.

Keywords: NGS, Genome, Ocular, Epithelial, Dry-eye

Research Title: Genetic study in a family with novel mutation in the gene sepiapterin reductase (SPR)

Author: Tawfiq Froukh, Published Year: 2019

European Human Genetics Conference 2019, Gothenburg, Sweden

Faculty: Science

Abstract: Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4). One Jordanian patient to first cousin parents is reported in this study. The parents of the proband have recognized the symptoms of their daughter at six months old with motor developmental delay. The symptoms were progressed after-then to include speech delay, seizure, ataxia, oculomotor apraxia, dysarthia and choreoathetosis. Despite of these symptoms, the clinicians in Jordan were unable to diagnose the case. In August 2018, the proband (8 years old) was presented to the department of biotechnology and genetic engineering at Philadelphia University in Jordan for the purposes of performing whole exome sequencing (WES). Analysis of WES data has revealed novel homozygous frameshift variant in the gene SPR (NM_003124.4:c.40delG,p.Ala15Profs*100). The variant is heterozygous in the parents and in the healthy male siblings. Therefore, the studied case was diagnosed with sepiapterin reductase deficiency. Because this disease is likely to be treated recommendations were given to the family immediately to start treatments trials. The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.

Keywords: Intellectual disability, Serotonin, Dopamine, Autosomal recessive, Genome.