Research Title: Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant Mycobacterium tuberculosis

Author: Balakumar Chandrasekarn, Published Year: 2021

Bioorganic Chemistry, 115

Faculty: Pharmacy

Abstract: Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.

Keywords: SynthesisMultidrug-resistant tuberculosisIsatinDockingMD simulations

Research Title: IN SILICO EVALUATION AND SYNTHESIS OF NOVEL SULFONAMIDES AS PROMISING ANTI-VIRAL LEAD MOLECULES DOCKED AGAINST ANTI-COVID-19 PROTEIN TARGETS: SARS-COV-2 MAIN PROTEASE

Author: Balakumar Chandrasekarn, Published Year: 2021

Faculty: Pharmacy

Abstract: COVID-19 pandemic has led us to design and develop novel organic molecules as medicinally promising lead molecules which can prevent the SARS-CoV-2 virus of the infected patients. The current invention provides potential anti-viral drugs docked against anti-COVID-19 protein targets: SARS-CoV-2 main protease, drug-likeness, efficacy, molecular docking, physicochemical and pharmacokinetic studies of novel synthesized sulfonamide analogues. Physicochemical and pharmacokinetic properties have been evaluated on the basis of certain parameters like Lipinski rule of 5 (RO5 rule) and ADMET (absorption, distribution, metabolism, excretion and toxicity). All the synthesized compounds follow Lipinski rule of five (RO5 rule) and the compounds followed the range of rotational bonds, hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), topological surface area (TPSA), and number of violations, etc. All these compounds shown good pharmacokinetic properties, zero renal OCT2 substrate toxicity and negligible toxicity values. BOILED-egg model was carried out for evaluating the gastrointestinal absorption and brain penetration effect. Compounds 3b and 3d comes under white region of egg and exhibited good gastrointestinal absorption, whereas, 3a, 3c, 3e and 3f compounds fall under yellow region (yolk) of egg which showed good brain penetration effect. All novel sulfonamide analogues including commercially available anti-COVID-19 drugs, Hydroxychloroquine and Umifenovir docked with anti-COVID-19 protein targets, i.e., PDB: 6VWW & 6Y2E. Compound 3c when docked with PDB: 6VWW shown maximum energy of -22.06 kcal/mol with two hydrogen binding interactions which are better than marketed drugs. Similarly, compound 3a exhibited highest energy of -14.00 kcal/mol.

Keywords: COMPUTER-AIDED DRUG DESIGN AND GREEN SYNTHESIS

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: 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