Research Title: Protein/Peptide Drug Delivery Systems: Practical Considerations in Pharmaceutical Product Development

Author: Balakumar Chandrasekarn, Published Year: 2019

Faculty: Pharmacy

Abstract: Proteins and peptides are involved in a wide range of vital functions and processes in the body that are essential for life. Proteins and peptides also have various roles in pathological conditions such as cancer and diabetes. Therefore, the use of proteins and peptides as therapeutic agents is considered as an attractive approach to combating various diseases. However, the physicochemical properties of proteins and peptides make them challenging for exogenous administration, especially by the oral route of administration. Various protein/peptide drug delivery systems have been extensively investigated to overcome the problems associated with the exogenous administration of protein and peptide therapeutics. In this chapter, different approaches for the delivery of proteins and peptides are discussed including chemical modifications, absorption enhancers, carrier systems, and various other approaches.

Keywords: Protein delivery nanoparticle carriers absorption enhancers PEGylation

Research Title: Synthesis of 4, 6-disubstituted pyrazolo [3, 4-d] pyrimidine analogues: Cyclin-dependent kinase 2 (CDK2) inhibition, molecular docking and anticancer evaluation

Author: Balakumar Chandrasekarn, Published Year: 2019

Journal of Molecular Structure , 1176

Faculty: Pharmacy

Abstract: The cyclin-dependent kinases (CDKs) play a crucial role in cell cycle progression and are validated targets of cancer therapy. Pyrazolopyrimidines are versatile scaffolds, which have been exploited for developing potential anticancer agents. We herein report the synthesis and in vitro CDK2/cyclin E kinase inhibitory activity of 34 novel 4,6-disubstituted pyrazolo [3,4-d]pyrimidines (9a-9s, 13a-13h, 14a-14d, 15a-15c). The structure-activity relationship (SAR) studies revealed that compounds with thiopentane/thiophenethyl group at C-6 and heteroatom-containing bicyclic moiety (benzofuran) at C-4 exhibited good CDK2 inhibitory activity. Further, the binding energies obtained for the active compounds from in silico molecular docking studies with CDK2 were found to be in consonance with the observed SAR and experimental results. In addition, some of the synthesized compounds showed anti-proliferative activity against K-562 (chronic myelogenous leukaemia) and MCF-7 (breast adenocarcinoma) cell lines in micromolar ranges. Further, the cytotoxicity studies on CHO cell line revealed that all the compounds are non-toxic to normal cells and are safe. Thus, the research findings revealed the anticancer potential of 4,6-disubstituted pyrazolo [3,4-d]pyrimidine derivatives which could be further considered for lead optimization.

Keywords: Pyrazolo[3,4-d]pyrimidine Cyclin-dependent kinase inhibitor Anti-proliferative activity Molecular docking GLIDE

Research Title: Recent Advances in the In-silico Structure-based and Ligand-based Approaches for the Design and Discovery of Agonists and Antagonists of A2A Adenosine Receptor

Author: Balakumar Chandrasekarn, Published Year: 2019

Current Pharmaceutical Design, 25

Faculty: Pharmacy

Abstract: A2A receptor belongs to the family of GPCRs, which are the most abundant membrane protein family. Studies in the last few decades have shown the therapeutic applications of A2A receptor in various diseases. In the present mini-review, we have discussed the recent progress in the in-silico studies of the A2A receptor. Herein, we described the different structures of A2A receptor, the discovery of new agonists and antagonists using virtualscreening/ docking, pharmacophore modeling, and QSAR based pharmacophore modeling. We have also discussed various molecular dynamics (MD) simulations studies of A2A receptor in complex with ligands.

Keywords: A2A receptor; GPCR; MD simulations; in-silico; pharmacophore modeling; virtual screening.

Research Title: 7‐Amino‐2‐aryl/hetero‐aryl‐5‐oxo‐5,8‐dihydro[1,2,4]triazolo[1,5‐a]pyridine‐6‐carbonitriles: Synthesis and adenosine receptor binding studies

Author: Balakumar Chandrasekarn, Published Year: 2019

Chemical Biology and Drug Design, 94

Faculty: Pharmacy

Abstract: A series of novel 7‐amino‐5‐oxo‐2‐substituted‐aryl/hetero‐aryl‐5,8‐dihydro[1,2,4]triazolo[1,5‐a]pyridine‐6‐carbonitriles (4a–4t) was synthesized, characterized and evaluated for their binding affinity and selectivity towards hA1, hA2A, hA2B and hA3 adenosine receptors (ARs). Compound 4a with a phenyl ring at 2‐position of the triazolo moiety of the scaffold showed high affinity and selectivity for hA1 AR (Ki hA1 = 0.076 μM, hA2A = 25.6 μM and hA3 > 100 μM). Introduction of various electron donating and withdrawing groups at different positions of the phenyl ring resulted in drastic reduction in affinity and selectivity towards all the ARs, except compound 4b with a 4‐hydroxyphenyl group at 2‐position. Interestingly, the replacement of the phenyl ring with a smaller heterocyclic thiophene ring (π excessive system) resulted in further improvement of affinity for hA1 AR of compound 4t (Ki hA1 = 0.051 μM, hA2A = 9.01 μM and hA3 > 13.9 μM) while retaining the significant selectivity against all other AR subtypes similar to compound 4a. The encouraging results for compounds 4a and 4t indicate that substitution at 2‐position of the scaffold with π‐excessive systems other than thiophene may lead to even more potent and selective hA1 AR antagonists.

Keywords: A1 adenosine receptors, adenosine receptor antagonists, cyanoacetic hydrazides, triazolopyridines

Research Title: Design and synthesis of novel heterofused pyrimidine analogues as effective antimicrobial agents

Author: Balakumar Chandrasekarn, Published Year: 2019

Journal of Molecular Structure , 1183

Faculty: Pharmacy

Abstract: A total of 66 novel heterofused pyrimidine analogues (pyrazolo[3,4-d]pyrimidine (7-43) and pyrido[2,3-d]pyrimidine (51a-l & 52a-h)) were synthesized by employing suitable methods. The desired structures of all the synthesized compounds were confirmed based on FT-IR, 1H NMR, 13C NMR and HRMS experimental data. Further, 19F NMR and 1H-15N HMBC of the representative compound were presented. All the final compounds were screened for their in vitro antitubercular (Mycobacterium tuberculosis; H37 Rv), antibacterial (S. aureus, B. subtilis, E. coli and P. aeruginosa) and antifungal (C. neoformans, C. albicans and A. niger) activities. Compounds 51d, 51j, 51k, 51l, and 51g displayed good antibacterial and antifungal activity (MIC = 12.5 μg/ml) against bacterial and fungal strains, while moderate inhibition (MIC = 59 μM) was observed for 51l against H37 Rv strain.

Keywords: Pyrazolo[3,4-d]pyrimidines Fluorinated pyrido[2,3-d]pyrimidines Antitubercular activity Antibacterial activity Antifungal activity

Research Title: Molecular modeling approaches for the discovery of adenosine A2B receptor antagonists: current status and future perspectives

Author: Balakumar Chandrasekarn, Published Year: 2019

Drug Discovery Today, 24

Faculty: Pharmacy

Abstract: Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belonging to the superfamily of G-protein-coupled receptors (GPCRs). Several molecular modeling approaches have been developed for A2BAR and its antagonists, from the construction of a homology model, molecular docking, molecular dynamics (MD) simulations, and 3D quantitative structure–activity relationship (QSAR) modeling to pharmacophore modeling, each of which has different objectives and outcomes. In this review, we provide a systematic outline of advances in molecular modeling approaches towards A2BAR for deducing its structure and interactions with various types of antagonist. The information, methods and perspectives presented here provides impetus for medicinal chemists to discover potential ligands that can bind selectively with higher affinity to A2BAR.

Keywords: Adenosine receptors

Research Title: Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA

Author: Balakumar Chandrasekarn, Published Year: 2019

Bioorganic and Medicinal Chemistry Letters, 29

Faculty: Pharmacy

Abstract: InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H37Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 µM concentration and IC50 of 2.82 µM against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe.

Keywords: Tuberculosis InhA inhibitor Carbazole Hybridization GLIDE Molecular dynamics

Research Title: Therapeutic Potentials of A2B Adenosine Receptor Ligands: Current Status and Perspectives.

Author: Balakumar Chandrasekarn, Published Year: 2019

Current Pharmaceutical Design, 25

Faculty: Pharmacy

Abstract: Background: Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belong to the superfamily of G-protein coupled receptors (GPCRs). More than 40% of modern medicines act through either activation or inhibition of signaling processes associated with GPCRs. In particular, A2B AR signaling pathways are implicated in asthma, inflammation, cancer, ischemic hyperfusion, diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, and kidney disease. Methods: This article reviews different disease segments wherein A2B AR is implicated and discusses the potential role of subtype-selective A2B AR ligands in the management of such diseases or disorders. All the relevant publications on this topic are reviewed and presented scientifically. Results: This review provides an up-to-date highlight of the recent advances in the development of novel and selective A2B AR ligands and their therapeutic role in treating various disease conditions. A special focus has been given to the therapeutic potentials of selective A2B AR ligands in the management of airway inflammatory conditions and cancer. Conclusions: This systematic review degnmonstrates the current status and perspectives of A2B AR ligands as therapeutically useful agents that would assist medicinal chemists and pharmacologists in discovering novel and subtype-selective A2B AR ligands as potential drug candidates.

Keywords: A2B adenosine receptor, asthma, cancer, diabetes, GIT disorders, G-protein coupled receptors (GPCRs).

Research Title: Human serum albumin interaction, in silico and anticancer evaluation ofPine-Gold nanoparticles

Author: Balakumar Chandrasekarn, Published Year: 2020

Process Biochemistry, 89

Faculty: Pharmacy

Abstract: Unique characteristics displayed by phytoconstituent conjugated nanoparticles and their crucial interactionswith proteins serve to develop nanoparticle-bio-interface platform. Gold nanoparticles of 16 nm in size weregenerated using aqueous extracts of pine bark and further conjugated to human serum albumin. The gold na-noparticles-protein complex was characterized by surface plasmon resonance, UV–vis and emission spectroscopytechniques. Further, it was characterized for surface morphology and elemental composition, crystallographicquality, nanoparticles size, shape, stability, structural determination and the identification of capping agent.Moreover, the interaction of gold nanoparticles with human serum albumin was investigated using conventionalspectroscopy techniques. Fluorescence quenching and absorption studies demonstrated an effective binding ofhuman serum albumin with oleamide capped gold nanoparticles. The molecular docking study showed a bindingaffinity of -6.1 kcal/mol whereas the molecular dynamics simulation indicated that the binding of oleamide tohuman serum albumin. A biological evaluation of pine bark extract-gold nanoparticles showed cytotoxicity withincreased cell mortality in lung cancer cells and minimal toxicity on non-cancerous human embryonic kidneycells, respectively.

Keywords: Pine bark extract Gold nanoparticles Human serum albumin HEK293 cells Oleamide

Research Title: TPGS-mediated one-pot synthesis, XRD structural analysis,antimicrobial evaluation and molecular docking of novel heterocycles as potential inhibitors of p53-MDM2 protein

Author: Balakumar Chandrasekarn, Published Year: 2019

Journal of Molecular Structure , 1202

Faculty: Pharmacy

Abstract: Novel heterocyclic bioactive small molecules bearing thioether moiety,fluorine containing dihydropyridine and dihydro pyran were synthesized and characterized using spectroscopic methods (FT-IR,1H,13C and19F NMR), LC-MS and SC-XRD. The reaction conducted is highly environment-friendly involvingD-a-Tocopherol polyethylene glycol succinate (TPGS) - Water binary solvent as reaction medium. All ofthe synthesizedfinal compounds were evaluated against 2 g-negative [Escherichia coli(ATCC 25922) andPseudomonas aeruginosa(ATCC 27853)] and 1 g-positive [Staphylococcus aureus(ATCC 29213)] bacterialstrains byin vitro. Molecular docking experiments were carried out against p53-MDM2 tumor suppressorprotein to gain more insights into the binding mode of thefinal compounds. In this study, we discoveredpotent p53-MDM2 inhibition by 2-thiobenzyl-3-formyl quinoline, 2-thio-1,2-dihydroquinoline-3-formylN-substituted thiosemi-carbazone andfluorine substituted new pyridine and pyran derivatives bystructure-based design

Keywords: XRD Molecular docking TPGS One-pot synthesis p53-MDM2 protein