Research Title: Target protein degradation by protacs: A budding cancer treatment strategy

Author: Balakumar Chandrasekarn, Published Year: 2023

Pharmacology & Therapeutics, 250

Faculty: Pharmacy

Abstract: Cancer is one of the most common causes of death. So, its lethal effect increases with time. Near about hundreds of cancers are known in humans. Cancer treatment is done to cure or prolonged remission, and shrinkage of the tumor. Cytotoxic agents, biological agents/targeted drugs, hormonal drugs, surgery, radiotherapy/proton therapy, chemotherapy, immunotherapy, and gene therapy are currently used in the treatment of cancer but their cost is high and cause various side effects. Seeing this, some new targeted strategies such as PROTACs are the need of the time. Proteolysis targeting chimera (PROTAC) has become one of the most discussed topics regarding cancer treatment. Few of the PROTAC molecules are in the trial phases. PROTACs have many advantages over other strategies such as modularity, compatibility, sub-stoichiometric activity, acting on undruggable targets, molecular design, and acts on intracellular targets, selectivity and specificity can be recruited for any cancer, versatility, and others. PROTACs are having some unclear questions on their pharmacokinetics, heavy-molecular weight, etc.

Keywords: PROTACs; Cancer; E3 ligases; Protein degradation; Ubiquitination

Research Title: Development and Characterization of Gel-Based Buccoadhesive Bilayer Formulation of Nifedipine

Author: Balakumar Chandrasekarn, Published Year: 2023

GELS, 9

Faculty: Pharmacy

Abstract: A promising controlled drug delivery system has been developed based on polymeric buccoadhesive bilayered formulation that uses a drug-free backing layer and a polymeric hydrophilic gel buccoadhesive core layer containing nifedipine. The DSC thermogravimetric analysis confirms the drug’s entrapment in the gel layer and reveals no evidence of a potential interaction. Various ratios of bioadhesive polymers, including HPMC K100, PVP K30, SCMC, and CP 934, were combined with EC as an impermeable backing layer to ensure unidirectional drug release towards the buccal mucosa. The polymeric compositions of hydrophilic gel-natured HPMC, SCMC, and CP formed a matrix layer by surrounding the core nifedipine during compression. Preformulation studies were performed for all of the ingredients in order to evaluate their physical and flow characteristics. Ex vivo buccoadhesive strength, surface pH, swelling index, in vitro and in vivo drug release, and ex vivo permeation investigations were performed to evaluate the produced gel-based system. Rapid temperature variations had no appreciable impact on the substance’s physical properties, pharmacological content, or buccoadhesive strength during stability testing using actual human saliva. It was clear from a histological examination of the ex vivo mucosa that the developed system did not cause any irritation or inflammation at the site of administration. The formulation NT5 was the best one, with a correlation coefficient of 0.9966. The in vitro and in vivo drug release profiles were well correlated, and they mimic the in vitro drug release pattern via the biological membrane. Thus, the developed gel-based formulation was found to be novel, stable, and useful for the targeted delivery of nifedipine.

Keywords: buccoadhesive; triggered delivery; ex vivo permeation; polymeric gel

Research Title: Combating Microbial Infections Using Metal-Based Nanoparticles as Potential Therapeutic Alternatives

Author: Balakumar Chandrasekarn, Published Year: 2023

Antibiotics, 12

Faculty: Pharmacy

Abstract: The nature of microorganisms and the efficiency of antimicrobials have witnessed a huge co-dependent change in their dynamics over the last few decades. On the other side, metals and metallic compounds have gained popularity owing to their effectiveness against various microbial strains. A structured search of both research and review papers was conducted via different electronic databases, such as PubMed, Bentham, Springer, and Science Direct, among others, for the present review. Along with these, marketed products, patents, and Clinicaltrials.gov were also referred to for our review. Different microbes such as bacteria, fungi, etc., and their diverse species and strains have been reviewed and found to be sensitive to metal-carrying formulations. The products are observed to restrict growth, multiplication, and biofilm formation effectively and adequately. Silver has an apt use in this area of treatment and recovery, and other metals like copper, gold, iron, and gallium have also been observed to generate antimicrobial activity. The present review identified membrane disruption, oxidative stress, and interaction with proteins and enzymes to be the primary microbicidal processes. Elaborating the action, nanoparticles and nanosystems are shown to work in our favor in well excelled and rational ways.

Keywords: metals; nanoparticles; antimicrobial action; microbicidal; biofilm formation inhibitors

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: 2023

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.

Keywords: Fluorophenyl-thiazoleChalconeMolecular dockingMolecular dynamicsADME properties

Research Title: Synthesis, pharmacological evaluation, and molecular modeling studies of novel isatin hybrids as potential anticancer agents

Author: Balakumar Chandrasekarn, Published Year: 2023

Journal of Saudi Chemical Society, 27

Faculty: Pharmacy

Abstract: A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N4 piperazine was found to be the most active with the promising IC50 (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.

Keywords: Isatin-pyrimidine hybridAntiproliferative activityBreast cancer cell (MCF-7)Dalton’s ascitic lymphoma (DAL)Molecular docking

Research Title: Development of a Polyherbal Topical Gel for the Treatment of Acne

Author: Balakumar Chandrasekarn, Published Year: 2023

GELS, 9

Faculty: Pharmacy

Abstract: The present work aimed to formulate and evaluate a polyherbal gel using Aloe barbadensis and extract of Vigna radiata for the treatment of acne, a disorder of the skin in which hair follicles and sebaceous glands are blocked, causing inflammation and redness of the skin. Aloe barbadensis pulp was collected and mixed with the extract of Vigna radiata and formulated into a gel using Carbopol 940, triethanolamine, and propylene glycol as the gelling agent, viscosity modifier, and pH modifier, respectively. The gel was evaluated for its antimicrobial properties against Staphylococcus aureus, Escherichia coli, and Candida albicans. Antimicrobial agents, such as gentamycin and fluconazole, were used as the standards. The developed formulation showed promising zone of inhibition. The gel was further evaluated for its physicochemical properties. The formulation showed a promising effect on acne together with the additive effect of Aloe barbadensis on skin.

Keywords: Aloe barbadensis; Vigna radiata; Carbopol 940; polyherbal gel; acne

Research Title: Topochemical studies on 4(3H)quinazolinones as dihydrofolate reductase (DHFR) inhibitors: An approach to predict the antitumour activity

Author: Balakumar Chandrasekarn, Published Year: 2013

International Journal of Medical & Pharmaceutical Sciences , 3

Faculty: Pharmacy

Abstract: Background of study: Inhibition of DHFR is one of the potential targets for anticancer therapy. In this study, topochemical descriptor based calculations were carried out on substituted 4(3H)-quinazolinones to predict DHFR inhibition. A data set of 50 molecules of substituted 4(3H)-quinazolinones as potential DHFR inhibitors and its topological descriptors like Wiener’s index, Balaban’s index and Molecular topological index were investigated. Objective: The topological data was systematically analyzed and suitable descriptor based topochemical models were developed after the identification of the active ranges. Research methodology: Subsequently, the DHFR inhibition activity was predicted for all the data set of molecules using topochemical models. Then, the predicted activity was compared with the experimentally reported DHFR inhibitor activity. Results: The overall prediction of DHFR inhibition was found to be higher accuracy of 80% for the models based on Wiener’s index as well as Molecular topological index and 74% for Balaban’s index. Conclusions: The prediction of DHFR inhibition using topochemical descriptors can be useful to design newer analogues of quinazolines as potential DHFR inhibitors.

Keywords: Dihydrofolate reductase, Wiener’s index, Balaban’s index, Molecular topological index and 4(3H)-quinazolinone, Antitumor action

Research Title: Antidiabetic activity of the aqueous extracts of Foeniculum vulgare on streptozotocin-induced diabetic rats

Author: Balakumar Chandrasekarn, Published Year: 2014

Int J Adv Pharm Biol Chem, 3

Faculty: Pharmacy

Abstract: Diabetes mellitus is a clinical syndrome associated with an abnormal high blood glucose concentration due to insufficient insulin secretion or defective in insulin action. The present study was attempted to evaluate the antidiabetic effects of Foeniculum vulgare in streptozotocin-induced diabetic rats.

Keywords: Antidiabetic activity; Foeniculum vulgare

Research Title: An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold

Author: Balakumar Chandrasekarn, Published Year: 2017

European Journal of Medicinal Chemistry, 126

Faculty: Pharmacy

Abstract: Pyrazolo[1,5-a]pyrimidine scaffold is one of the privileged hetrocycles in drug discovery. Its application as a buliding block for developing drug-like candidates has displayed broad range of medicinal properties such as anticancer, CNS agents, anti-infectious, anti-inflammatory, CRF1 antagonists and radio diagnostics. The structure-activity relationship (SAR) studies have acquired greater attention amid medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is plenty of room for the medicinal chemists to further exploit this privileged scaffold in developing potential drug candidates. The present review briefly outlines relevant synthetic strategies employed for pyrazolo[1,5-a]pyrimidine derivatives. It also extensively reveals significant biological properties along with SAR studies. To the best of our understanding current review is the first attempt made towards the compilation of significant advances made on pyrazolo[1,5-a]pyrimidines reported since 1980s.

Keywords: Pyrazolo[1,5-a]pyrimidineAnti-cancer agentsAnti-infectious agentsCNS agentsAnti-inflammatory agentsRadiopharmaceuticals

Research Title: Synthesis, antiproliferative activity and docking study of novel rhodanine derivatives as Bcr-Abl T1351 inhibitors

Author: Balakumar Chandrasekarn, Published Year: 2017

Research on Chemical Intermediates, 43

Faculty: Pharmacy

Abstract: A series of novel N-substituted rhodanines 6a–g were synthesized by a microwave synthesizer, and evaluated for their anti-proliferative activity. Most of the compounds showed inhibition against K562 cells in a dose-dependent manner and in particular compounds 6a, 6b and 6f exhibited most potent activity with an IC50 value of 19.62, 24.01 and 22.91 µg/ml by MTT assay. Further in silico docking studies of the above compounds against Bcr-Abl T1351 protein showed good binding affinity, thus indicating that the compounds behave as third generation inhibitors. A dose-dependent increase in LDH release upon treatment with 6a–g complements the MTT assay for anti-proliferative activity. Flow cytometry of 6a showed that it interferes with the cell division by indicating G1 phase arrest followed by apoptosis.

Keywords: Synthesis; antiproliferative activity; docking; rhodanine derivatives