Research Title: Computer aided drug design and green synthesis of novel pyrazole analogues as potential SARS-CoV-2 main protease inhibitors against anti COVID-19 protein targets

Author: Balakumar Chandrasekarn, Published Year: 2021

Faculty: Pharmacy

Abstract: COVID-19 pandemic has significantly increased high deaths, infectivity and hospitalizations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a foremost problem in the world presently. Currently, all research institutions and pharmaceutical industries are keen in developing new vaccines and more effective drugs that could inhibit the SARS-CoV-2 virus and help in the treatment of patients. This provoked us to design medicinally effective drug candiadates which can prevent the SARS-CoV-2 virus of the infected patients. The present invention offers most promising anti-viral drugs docked against anti-COVID-19 protein targets: SARS-CoV-2 main protease, efficacy, drug-likeness, molecular docking, BOILED-EGG model, physicochemical and pharmacokinetic studies of novel synthesized polysubstituted 4,7-dihydro 1H-pyrazolo[3,4-b]pyridin-6-amine analogues. All the novel synthesized analogues including commercially available anti-COVID-19 drugs, Hydroxychloroquine and Umifenovir docked with anti-COVID-19 protein targets, i.e., PDB: 6LU7 and 6Y2E. This current invention further provides a rapid access to novel 4,7-dihydro-H-pyrazolo[3,4-b]pyridin-6-amines and few advantages are milder reaction conditions, short reaction times, easy work-up, excellent yields, effective SARS-CoV-2 main protease inhibitors and use of ultrasonic radiation via green synthesis.

Keywords: COMPUTER-AIDED DRUG DESIGN AND GREEN SYNTHESIS

Research Title: Appraising the therapeutical potentials of Alchornea laxiflora (Benth.) Pax & K. Hoffm., an underexplored medicinal herb: A systematic review

Author: Balakumar Chandrasekarn, Published Year: 2022

Frontiers in Pharmacology, 13

Faculty: Pharmacy

Abstract: Ethnopharmacological relevance: Alchornea laxiflora (Benth.) Pax & K. Hoffm. (Euphorbiaceae) is an important traditional medicinal plant grown in tropical Africa. The stem, leaves, and root have been widely used in the folk medicine systems in Nigeria, Cameroon, South Africa, and Ghana to treat various ailments, including inflammatory, infectious, and central nervous system disorders, such as anxiety and epilepsy. Material and methods: The scientific name of the plant was validated using the “The Plant List,” “Kew Royal Botanic Gardens,” and Tropicos Nomenclatural databases. The literature search on A. laxiflora was performed using electronic search engines and databases such as Google scholar, ScienceDirect, PubMed, AJOL, Scopus, and Mendeley. Results: To the best of our knowledge, no specific and detailed review has been reported on A. laxiflora. Consequently, this review provides an up-to-date systematic presentation on ethnobotany, phytoconstituents, pharmacological activities, and toxicity profiles of A. laxiflora. Phytochemical investigations disclosed the presence of important compounds, such as alkaloids, flavonoids, phenolics, terpenoids, and fatty acids. Furthermore, various pharmacological activities and traditional uses reported for this botanical drug were discussed comprehensively. Conclusion: This systemic review presents the current status and perspectives of A. laxiflora as a potential therapeutic modality that would assist futureresearchers in exploring this African botanical drug as a source of novel drug candidates for varied diseases.

Keywords: Alchornea laxiflora, ethnopharmacology, African plants, traditional medicine, phytochemistry, pharmacology

Research Title: One-step synthesis of picolinohydrazides from fusaric acid: DFT, structural characterization and molecular inhibitory studies on metastatic tumor-derived exosomal and non-exosomal proteins

Author: Balakumar Chandrasekarn, Published Year: 2022

Journal of Molecular Structure, 1225

Faculty: Pharmacy

Abstract: A new class of picolinohydrazide analogs (5–7) was synthesized via the one-pot reaction between fusaric acid (1) and aryl hydrazines (2–4) using amide coupling reagents. The synthesized compounds (5–7) were characterized using density-functional theory (DFT) computational spectroscopy, and instrumental methods. Global and local reactivity descriptors of these compounds were calculated at the B3LYP/6–311++g(d) level of theory to predict the reactivity and the reactive sites. The evaluated electronic properties (HOMO and LUMO) gave an insight into the molecular properties of the molecule. The charge distribution and molecular electrostatic potential facilitated the prediction of either the electrophilic or nucleophilic reactivity of these compounds. Extracellular heat shock protein-90 (HSP90) plays an essential role in tumor invasion while epidermal growth factor receptor (EGFR) is found at high levels on the surface of metastatic tumors. Blocking EGFR and HSP90 may predict metastatic spread. Molecular docking and molecular dynamics showed that picolinohydrazide analogs (5–7) act as inhibitors to the active-site cavity of the target proteins, i.e., EGFR and HSP90. The fluorine scaffold (6) has a potential binding free energy of -31.01 kcal mol−1 and -30.54 kcal mol−1 for EGFR and HSP90, respectively. The binding complex of fluorine scaffold (6) with EGFR and HSP90, respectively has also shown substantial stability in the post-dynamics analysis. Our results implicate the potential efficacy of novel adjunct therapeutic insights in treating advanced cancer.

Keywords: ExosomesDFTMolecular dockingMolecular dynamics simulationEGFRHSP90

Research Title: Standardization, in-silico and in-vivo safety assessment of methanol extract of Ziziphus mauritiana Lam leaves

Author: Balakumar Chandrasekarn, Published Year: 2022

Regulatory Toxicology and Pharmacology, 131

Faculty: Pharmacy

Abstract: Ziziphus mauritana Lam leaves were used to treat asthma, diabetes, pain, and inflammation in the Indian traditional system of medicine. The leaves of the Ziziphus mauritiana Lam were consumed as a vegetable in Indonesia and India. The present study aims to predict the pharmacokinetic properties of flavonoids identified & quantified through U(H)PLC and to evaluate the safety of methanol extract of Ziziphus mauritana Lam leaves (MEZ) in rats. A U(H)PLC-ESI-QTOF-MS/MS was performed to identify flavonoids present in MEZ and quantified using U(H)PLC method. The in-silico ADME properties of the flavonoids were analyzed using Schrodinger Maestro software. The acute oral toxicity study was performed by administering a single dose of MEZ (5000 mg/kg) in female rats and observed for 14 days. The sub-chronic studies were carried out by oral administration of MEZ at 500, 750, and 1000 mg/kg daily for 90 days. The changes in hematological parameters, clinical biochemistry, and histopathology were observed after the treatment period. Eight flavonoids rutin, kaempferol, luteolin, myricetin, catechin, and apigenin were identified from were identified in UPLC-QTOF-MS/MS analysis. These results showed the highest amount of luteolin (5.41 μg/ml) and kaempferol (4.02 μg/ml) present in MEZ. No signs of toxicity or mortality were observed in acute toxicity studies. In the sub-chronic studies, data showed that MEZ does not produce any changes in hematological and clinical biochemical parameters compared to control rats. MEZ (1000 mg/kg) significantly (p < 0.05) reduced total cholesterol, triglycerides, in male rats, which was more prominent on day 90. The histopathological analysis also revealed no changes in the vital organs. These results conclude that MEZ was considered safe and well-tolerated in rats.

Keywords: Ziziphus mauritiana Lam Biochemical Hematology Histopathology Toxicity

Research Title: Pharmacological and Biochemical Perspectives of Kinase Inhibitors in Cancer and COVID-19 Therapeutics

Author: Balakumar Chandrasekarn, Published Year: 2022

Frontiers in Pharmacology, 13

Faculty: Pharmacy

Abstract: Kinases are the component of superfamily enzymes known as phosphotransferases which involve transferring a phosphate group from phosphate-releasing high energy molecules to the specific substrates (Ardito et al., 2017). Kinases have significant roles in cell signalling, metabolism, cell transport, protein regulation, and other cellular events (Cohen, 2001).

Keywords: COVID-19, kinase inhibitors, CDK, ligand-based and structure-based drug design, pharmacology

Research Title: IN SILICO INVESTIGATION OF NATURAL PHYTOCONSTITUENTS OF TERMINALIA CHEBULA AGAINST COVID-19

Author: Balakumar Chandrasekarn, Published Year: 2023

ANNALS OF FOREST RESEARCH, 66

Faculty: Pharmacy

Abstract: Coronavirus Disease-2019 (COVID-19) caused by the SARS-CoV-2 type of virus has scrambled the entire world with its mortality rate. Since it is a global pandemic, US-FDA endorsed the use of broad-spectrum antiviral medicationremdesivir from Gilead Sciences for its treatment. Recently, Molnupiravir tablets from Merck company got approval from the Britain has attracted the scientific community to find newer agents for the treatment of COVID-19. One of the important validated targets for designing and developing a new drug against COVID-19 is the main protease of SARSCoV In parallel, the knowledge of traditional medicines has been re-evaluated and can be considered to identify novel and effective approaches for the treatment of COVID-19. In our study,we have selected ten phytoconstituents from Terminalia chebula as potent inhibitors of the enzyme protease. In silico molecular investigation through the use of molecular docking was conducted and determined that constituents such as chebulic acid and corilagin showed strong interactions with the key amino acid residues (Cys145 and His41) with the binding affinities of -6.1kcal/mol and -9.0kcal/mol, respectively. ADMET analysis demonstrated the safety profiles for the identified natural phytoconstituents of Terminalia chebula. The molecular dynamics simulation showed that chebulic acid and corilagin are good candidates as inhibitors.

Keywords: Terminalia chebula, COVID-19, SARS-CoV-2 protease, ADMET, chebulic acid.

Research Title: Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review

Author: Balakumar Chandrasekarn, Published Year: 2023

Frontiers in Pharmacology, 14

Faculty: Pharmacy

Abstract: Severe cases of COVID-19 are characterized by hyperinflammation induced by cytokine storm, ARDS leading to multiorgan failure and death. JAK-STAT signaling has been implicated in immunopathogenesis of COVID-19 infection under different stages such as viral entry, escaping innate immunity, replication, and subsequent inflammatory processes. Prompted by this fact and prior utilization as an immunomodulatory agent for several autoimmune, allergic, and inflammatory conditions, Jakinibs have been recognized as validated small molecules targeting the rapid release of proinflammatory cytokines, primarily IL-6, and GM-CSF. Various clinical trials are under investigation to evaluate Jakinibs as potential candidates for treating COVID-19. Till date, there is only one small molecule Jakinib known as baricitinib has received FDA-approval as a standalone immunomodulatory agent in treating critical COVID-19 patients. Though various meta-analyses have confirmed and validated the safety and efficacy of Jakinibs, further studies are required to understand the elaborated pathogenesis of COVID-19, duration of Jakinib treatment, and assess the combination therapeutic strategies. In this review, we highlighted JAK-STAT signalling in the pathogenesis of COVID-19 and clinically approved Jakinibs. Moreover, this review described substantially the promising use of Jakinibs and discussed their limitations in the context of COVID-19 therapy. Hence, this review article provides a concise, yet significant insight into the therapeutic implications of Jakinibs as potential anti-COVID agents which opens up a new horizon in the treatment of COVID-19, effectively.

Keywords: Janus kinase, JAKs, JAK-STAT pathway, JAKi, Jakinibs, kinase inhibitors, COVID-19, SARS-CoV-2

Research Title: Novel fluorophenyl tethered thiazole and chalcone analogues as potential anti-tubercular agents: Design, synthesis, biological and in silico evaluations

Author: Balakumar Chandrasekarn, Published Year: 2022

Journal of Molecular Structure, 1276

Faculty: Pharmacy

Abstract: Novel analogues of fluorophenyl tethered thiazoles 7a-k and chalcones 10a-k were designed through molecular hybridization approach. All the synthesized final compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Rv strain. Among the two series, compound 10g displayed potent inhibition with MIC99 of 1.56 µM against parental and isoniazid-resistant strains of M. tuberculosis. Further, the same compound inhibited the growth of intracellular M. tuberculosis. To gain an insight into the molecular mechanism of actions, in silico molecular docking experiments were conducted using the molecular structure of the DNA gyrase enzyme, which revealed crucial interactions. This was further substantiated through molecular dynamics simulation study of the mycobacterial DNA Gyrase protein against the lead compound 10g and the reference drug (CFX-Ciprofloxacin). Furthermore, the drug-likeliness of the synthesized compounds was computed based on Lipinski's rule of five and ADME pharmacokinetic parameters. Thus, a chalcone-based lead 10g was identified in our study and showed promising antitubercular activity with drug-like properties. The identified lead molecule could act as a starting point to develop novel, potent antitubercular agents against the parental and drug-resistant tuberculosis strains.

Keywords: Fluorophenyl-thiazoleChalconeMolecular dockingMolecular dynamicsADME properties

Research Title: Textual analysis of the annual report and corporate performance: evidence from China

Author: Fahd Mohammed Saleh Al-Duais, Published Year: 2022

Financial, business and sustainable development environment in light of the Corona pandemic, Ma'an

Faculty: Business

Abstract: Purpose This paper aims to examine the relationship between the readability of annual reports and corporate performance in Chinese listed firms. Design/methodology/approach This research examined the annual report readability factors of Chinese listed companies by using a textual analysis method using Python to extract the text from the annual reports, convert it into numerical form to facilitate statistical analysis and then merge the results with data from the Chinese stock market to explain the impact on corporate performance and predict future earnings in the Chinese financial markets from 2008 to 2021. Findings Study findings indicate that firms with better financial reporting readability are more profitable, incur lower agency costs and have low earnings in the Chinese stock markets when readability is low (i.e. more complexity and length of annual reports). It was also found that when a listed company has a good performance, it prefers to use a short space to explain its operating and financial status. More generally, the means of the report length are short, and accounting terms are used less frequently; in the case of a poor company, the annual report is particularly long and accounting terms are more frequently used. In the context of the COVID-19 crisis, this study served as a proxy measure of returns prior to the announcement of the COVID-19 pandemic. In addition, an instrumental variable approach is used, which helps results to remain robust and control for fixed effects and potential endogeneity problems. Research limitations/implications Although this study’s results cannot be generalised globally because of their limited scope, they can still be generalised across non-English speaking countries. Thus, future cross-country research is encouraged to examine the textual analysis of financial reports across those countries. Practical implications This study conveys two messages to investors and policymakers within the Chinese market. First, investors ought to pay greater attention to the nonfinancial information contained in annual reports to improve the accuracy of their predictions regarding future firm performance. Second, Chinese policymakers are encouraged to instate a policy for the use of plain English in annual reports to make them more readable by international investors. Originality/value This study contributes to the paucity of research that examines English-written annual reports in non-English-speaking countries by examining the readability of annual reports in the Chinese market.

Keywords: Readability, Annual financial report, Corporate performance, Text analysis, Future earnings, Chinese listed companies

Research Title: The impact of information sharing on the quality of decision-making: From the point of view of employees in Jordanian private hospitals

Author: Fahd Mohammed Saleh Al-Duais, Published Year: 2023

Cogent Business & Management , 10(1)

Faculty: Business

Abstract: This paper examines how information sharing impacts the quality of decision-making in Jordanian private hospitals from the point of view of employees. It involved a structured questionnaire, which consisted of demographic data, information sharing, and decision-making. The research results suggest that sharing information in both common and unique situations significantly positively influences the decision-making abilities of teams. Merely possessing unique information does not enhance the ability to make decisions; conversely, common information is crucial to facilitate the decision-making process. Participant characteristics have no effect on decision-making quality, especially as team functional diversity continues to rise, with information sharing even less relevant as a result. Our results indicate that participants’ characteristics do not predict whether the discussion of shared information will contribute to decision-making quality. As a practical contribution, our findings recognise the importance of decision teams in information management, encourage flexibility and openness in organisational relations, and assist policymakers, managers, and regulators through training programs that confirm participation is one of the most important components of generating new ideas.

Keywords: Information sharing, decision making, common information, unique information, Jordanian hospitals.