Research Title: Ethics and Legal Protection of Uses of Computer Applications in Pharmaceutical Research

Author: Balakumar Chandrasekarn, Published Year: 2018

Faculty: Pharmacy

Abstract: The use of computer applications in pharmaceutical research is an essential approach nowadays, where it acts as a valuable vehicle in the successful journey of entire research. Despite the numerous advancements and benefits of computer technologies and algorithms, they are posting unanticipated legal, social, and ethical issues which are continuously rising to the individual and professional level. In this chapter, we focus mainly on the ethical issues and how legal protection can be applied to computer technologies and applications. This chapter begins with an outline of philosophers’ points of views and understandings in the field of computer ethics. Several important codes of conduct pertinent to the use of computers of some important organizations are also discussed. Different classes of ethical issues posted by philosophers, such as privacy, liability, ownership, and power, are also discussed. Finally, the main intellectual property rights (IPRs) applicable to the use of computers in different areas of the pharmaceutical research, namely, patents, copyrights, and protection of databases are also emphasized.

Keywords: Computer ethics ethical issues computer technology pharmaceutical research philosophy intellectual property rights

Research Title: Basics of Crystallization Process Applied in Drug Exploration

Author: Balakumar Chandrasekarn, Published Year: 2018

Faculty: Pharmacy

Abstract: The crystallization process is both an art and science which includes various techniques starting from simple sublimation to laser-induced methods. The science behind the crystallization is marvelous. It commences from simple nucleation and proceeds through a number of stages following the Ostwald’s law to develop into different crystal habits with distinguishing properties. The utilities of these crystals with specific properties are enormous in the pharmaceutical field. It ranges from improved micrometric properties, chemical stability, kinetic profile, bioavailability to a synergistic effect in cocrystals of two beneficial drug candidates. Since in drug discovery, the success rate is too meager, in spite of heavy labor, time, and financial investments, crystallization has emerged as a successful alternative technique to optimize the properties of available drugs. This chapter summarizes the basic concepts/mechanisms of crystallization, crystal habits, energetics of crystallization, crystallization techniques, crystallization problems, crystals characterization techniques, and their pharmaceutical applications.

Keywords: Crystallizationmechanisms of crystallization crystallization techniques applications of crystallization in drug research

Research Title: Computer-Aided Prediction of Pharmacokinetic (ADMET) Properties

Author: Balakumar Chandrasekarn, Published Year: 2018

Faculty: Pharmacy

Abstract: The development of new drug candidates is really a very expensive process that consumes time and effort. Hence, there is an urgent need to develop new methods that are capable of predicting the important pharmacokinetic properties of drugs in a rapid and more accurate manner before being synthesized. Various computational models have emerged for the purpose of predicting ADMET (absorption, distribution, mechanism, excretion, and toxicity) parameters of drugs and drug-like compounds. This chapter focuses mainly on the characterization of the modern in silico techniques that predict the behavior of drugs during the early stages of drug discovery and development and the purposes, needs, and objectives of ADMET studies, which in turn facilitates the discovery of new drugs with more desired absorption, distribution, metabolism, and excretion profiles in addition to the least toxic effects. This chapter also provides an insight into the physicochemical parameters affecting the ADMET of drugs including the solubility, lipophilicity, permeability, as well as the hydrogen bonding. The in silico prediction of the active transport of drugs through various transporter types (P-gp, BCRP, nucleoside transporter, hPEPT1, hASBT, OCTs, OATPs, and BBB choline transporter) is also discussed. The recent in silico tools that are used in the modern ADMET software along with the future perspective and challenges are also covered.

Keywords: In silico models ADMET properties pharmacokinetics physicochemical parameters computational modeling QSAR

Research Title: An appraisal on synthetic and pharmaceutical perspectives of pyrazolo [4, 3-d] pyrimidine scaffold

Author: Balakumar Chandrasekarn, Published Year: 2018

Bioorganic and Medicinal Chemistry , 26

Faculty: Pharmacy

Abstract: Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956.

Keywords: Pyrazolo[4,3-d]pyrimidine Synthetic strategies Anti-cancer agents Anti-infectious agents PDE-5 inhibitors Cytokinin antagonists

Research Title: Synthesis and adenosine receptors binding studies of new fluorinated analogues of pyrido[2,3-d]pyrimidines and quinazolines

Author: Balakumar Chandrasekarn, Published Year: 2018

Medicinal Chemistry Research, 27

Faculty: Pharmacy

Abstract: A series of new fluorine containing pyrido[2,3-d]pyrimidines and imidazo[1,2-c]pyrido[3,2-e]pyrimidines along with a series of bioisosteric fluorinated quinazolines were synthesised following appropriate synthetic schemes and characterised by spectral analytical means. X-ray crystal structure of the key precursor 1 (2-amino-3-cyano-4-trifluoro-methyl-6-phenyl-pyridine) was also determined to gain insight into its reactivity. Binding affinity data of all the compounds for adenosine receptors (ARs) showed that pyrido[2,3-d]pyrimidine scaffold with free amino (NH2) group at 2- and 4-position (2a) exhibited the maximum binding affinity for hA3 AR with similar affinity for the hA1 and somewhat lower affinity for hA2A ARs resulting in a compound with no A3 selectivity vs. A1 and moderate selectivity vs. A2A AR (K i hA1 = 0.62 µM, hA2A = 3.59 µM and hA3 = 0.42 µM). Interestingly, the replacement of both the amino groups with carbonyl (C=O) groups (compound 4) resulted in significantly improved affinity for hA1 AR but with moderate selectivity against hA2A and hA3 ARs (K i hA1 = 0.17 µM, hA2A = 0.67 µM and hA3 = 0.68 µM). In case of fluorinated quinazolines, only compound 18a showed remarkable affinity for hA1 AR with significant selectivity against hA2A and hA3 ARs (K i hA1 = 0.73 µM, hA2A > 30 µM and hA3 = 9.27 µM). The preliminary results of these compounds demonstrate that the fluorinated pyrido[2,3-d]pyrimidine and imidazo[1,2-c]pyrido[3,2-e]pyrimidine can be considered as promising scaffolds for further optimisation in search of potential antagonists with better affinity and selectivity towards hA1 and hA3 ARs.

Keywords: adenosine receptors pyrido[2,3‐d]pyrimidine

Research Title: Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3‐d]pyrimidine derivatives

Author: Balakumar Chandrasekarn, Published Year: 2018

Chemical Biology and Drug Design, 91

Faculty: Pharmacy

Abstract: A series of new molecules containing a thieno[2,3‐d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2‐position as well as an oxo‐group, imidazole or 1,2,4‐triazole ring at 4‐position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17–19 with a free amino group at 2‐position along with the presence of an imidazole/1,2,4‐triazole ring at 4‐position of the scaffold showed selective binding affinities for hA2A AR, whereas carbamoylation of the amino group at 2‐position (in the presence of an oxo‐group at 4‐position of the scaffold) increased the affinity and selectivity of certain compounds (7–10) for hA3 AR. Molecular dynamic simulation study of one of the most active compound 8 (Ki hA1 > 30 μm, hA2A = 0.65 μm, and hA3 = 0.124 μm) revealed the role of important amino acid residues for imparting good affinity towards hA3 and hA2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA2A AR and a homology model of hA3 AR to rationalize their structure–activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.

Keywords: adenosine receptors binding homology modelling molecular docking molecular dynamics thieno[2,3‐d]pyrimidine

Research Title: Crystal structure of the Eg5-K858 complex and implications for structure-based design of thiadiazole-containing inhibitors

Author: Balakumar Chandrasekarn, Published Year: 2018

European Journal of Medicinal Chemistry , 156

Faculty: Pharmacy

Abstract: The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

Keywords: 1,3,4-thiadiazoleK858 enantiomersEg5Antimitotic drugsEg5-K858 complexRational drug design

Research Title: Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors

Author: Balakumar Chandrasekarn, Published Year: 2018

Bioorganic Chemistry , 79

Faculty: Pharmacy

Abstract: A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7–43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure–activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.

Keywords: Pyrazolo[3,4-d]pyrimidineCyclin dependent kinase inhibitorAnti-proliferative activityMolecular dockingGLIDE

Research Title: Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5

Author: Balakumar Chandrasekarn, Published Year: 2018

Bioorganic and Medicinal Chemistry Letters, 28

Faculty: Pharmacy

Abstract: A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a–v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2 µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2 µM and 20.2 µM, respectively. A brief structure–activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein–ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a–v were also calculated based on the Lipinski’s rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development.

Keywords: 1,3,4-Thiadiazole-thiazolone MT-stimulated ATPase of Eg5 Hybridization Knoevenagel condensation GLIDEADME prediction

Research Title: Copper‐Catalyzed Self‐Condensation of Benzamide: Domino Reactions towards Quinazolinones

Author: Balakumar Chandrasekarn, Published Year: 2018

European Journal of Organic Chemistry, 2018

Faculty: Pharmacy

Abstract: We herein report a simple and highly efficient microwave‐assisted, copper‐catalyzed and ligand‐free synthetic method for 2‐substituted 4(3H)‐quinazolinones as domino reaction. This reaction proceeds via self‐condensation of substrate (2‐bromo/iodo benzamide) in the presence of a strong base and copper catalyst. The substituted quinazolinones were obtained in one‐pot reaction by intramolecular cyclization (condensation) via Ullmann–type intermediate. Both the intermediates and quinazolinones were obtained in good yield and can be further used as building blocks for developing the potential novel drug‐like compounds.

Keywords: copper‐catalyzed and ligand‐free synthetic method