Department of Pharmacy

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1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design
(Taylor & Francis, 2021-04) Murugesan, Sankaranarayanan
Cancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design.
1-(m-Chlorophenyl)piperazine induces depressogenic-like behaviour in rodents by stimulating the neuronal 5-HT2A receptors: Proposal of a modified rodent antidepressant assay
(Elsevier, 2009-04) Mahesh, R.
1-(m-Chlorophenyl)piperazine (mCPP) has a fairly complex neuropsychopharmacological profile owing to its affinity to multiple serotonergic receptors. This investigation was designed to establish the effect of mCPP on rodent depression-like behaviour. mCPP was screened in a rodent behavioural test battery comprising of validated antidepressant assays and interaction studies with conventional antidepressants and ligands were carried out in forced swim and tail suspension test (in mice). mCPP (1 mg/kg, i.p.) exhibited depressant-like effects in forced swim and tail suspension test (in mice), without influencing the locomotor status. Potentiation of 5-hydroxytryptophan/pargyline induced head twitches (in mice) and hyperthermic effects (in rats) were observed at the same dose level. Further, the behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic mCPP (1–2 mg/kg) treatment as observed from the modified open field, elevated plus maze and social interaction paradigms. Interaction studies revealed that the mCPP induced depressant-like effects were reversed by ketanserin, escitalopram, amitriptyline, ziprasidone, venlafaxine pretreatments but not by bupropion, harmane, ondansetron, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and MK-801. In conclusion, this study provided ample evidence that the stimulation of 5-HT2A receptors underlies the depressogenic-like effect of mCPP. Finally, the mCPP induced depression-like behaviour in rodents is envisaged as a modified antidepressant assay to identify novel serotonergic antidepressants.
2, 2-Bis (hydroxymethyl) propionic acid based cyclic carbonate monomers and their (co) polymers as advanced materials for biomedical applications
(Elsevier, 2021-08) Chitkara, Deepak; Mittal, Anupama
Designing grafted biodegradable polymers with tailored multi-functional properties is one of the most researched fields with extensive biomedical applications. Among many biodegradable polymers, polycarbonates have gained much attention due to their ease of synthesis, high drug loading, and excellent biocompatibility profiles. Among various monomers, 2,2-bis(hydroxymethyl) propionic acid (bis-MPA) derived cyclic carbonate monomers have been extensively explored in terms of their synthesis as well as their polymerization. Since the late 90s, significant advancements have been made in the design of bis-MPA derived cyclic carbonate monomers as well as in their reaction schemes. Currently, bis-MPA derived polycarbonates have taken a form of an entire platform with a multitude of applications, the latest being in the field of nanotechnology, targeted drug, and nucleic acid delivery. The present review outlines an up to date developments that have taken place in the last two decades in the design, synthesis, and biomedical applications of bis-MPA derived cyclic carbonates and their (co)polymers
2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carboxylic acids: Novel 5-HT3 receptor antagonists with anxiolytic-like activity in rodent behavioral models
(Candian Journal, 2013-06) Mahesh, R.
The aim of this study was to investigate the anxiolytic potential of a series of novel carboxylic acid based 1,8 naphthyridines as 5-HT3 receptor antagonists. The pA2 values of all the compounds were determined against agonist 2-methyl-5-hydroxytryptamine in longitudinal muscle myenteric plexus preparations from guinea pig ileum. Compounds with higher pA2 values, particularly those greater than ondansetron, a standard 5-HT3 receptor antagonist, and optimal log P values were screened in mice by using behavioral tests such as a light–dark (L/D) aversion test, elevated plus maze (EPM) test, and an open field test (OFT). In the L/D test, compounds 7a, 7b, 7d, 7e, and 7i (2 mg/kg body mass, intraperitoneal) significantly (P < 0.05) increased the latency time to leave the light compartment, total time spent in the light compartment, and the number of transitions between the light and dark compartments. Compounds 7a, 7d, 7f, 7h, and 7i (2 mg/kg, i.p.) significantly (P < 0.05) increased the time spent in the open arms and the number of entries into the open arms in the EPM test. In addition, compounds 7a, 7d, 7e, 7f, and 7h (2 mg/kg, i.p.) significantly (P < 0.05) increased the ambulation scores and the frequency of rearing in the OFT.
2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carboxylic acids: Novel 5-HT3 receptor antagonists with anxiolytic-like activity in rodent behavioral models
(CSP, 2013-06) Mahesh, R.
The aim of this study was to investigate the anxiolytic potential of a series of novel carboxylic acid based 1,8 naphthyridines as 5-HT3 receptor antagonists. The pA2 values of all the compounds were determined against agonist 2-methyl-5-hydroxytryptamine in longitudinal muscle myenteric plexus preparations from guinea pig ileum. Compounds with higher pA2 values, particularly those greater than ondansetron, a standard 5-HT3 receptor antagonist, and optimal log P values were screened in mice by using behavioral tests such as a light–dark (L/D) aversion test, elevated plus maze (EPM) test, and an open field test (OFT). In the L/D test, compounds 7a, 7b, 7d, 7e, and 7i (2 mg/kg body mass, intraperitoneal) significantly (P < 0.05) increased the latency time to leave the light compartment, total time spent in the light compartment, and the number of transitions between the light and dark compartments. Compounds 7a, 7d, 7f, 7h, and 7i (2 mg/kg, i.p.) significantly (P < 0.05) increased the time spent in the open arms and the number of entries into the open arms in the EPM test. In addition, compounds 7a, 7d, 7e, 7f, and 7h (2 mg/kg, i.p.) significantly (P < 0.05) increased the ambulation scores and the frequency of rearing in the OFT.
2-Amino Thiazole Derivatives as Prospective Aurora Kinase Inhibitors against Breast Cancer: QSAR, ADMET Prediction, Molecular Docking, and Molecular Dynamic Simulation Studies
(ACS, 2023-11) Murugesan, Sankaranarayanan
The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure–activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson’s electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a–e, 2a–e, 3a–e, 4a–e, 5a–e, and 6a–e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (−9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.
2-Substituted 4,5-dihydrothiazole-4-carboxylic acids are novel inhibitors of metallo-β-lactamases
(Elsevier, 2022-10) Sundriyal, Sandeep
Bacterial resistance to β-lactam antibiotics caused by class B metallo-β-lactamases (MBL), especially for certain hospital-acquired, Gram-negative pathogens, poses a significant threat to public health. We report several 2-substituted 4,5-dihydrothiazole-4-carboxylic acids to be novel MBL inhibitors. Structure activity relationship (SAR) and molecular modeling studies were performed and implications for further inhibitor design are discussed.
4i (N-(3-Chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist alleviates depressive behavior evoked in streptozotocin-induced diabetic mice: Role of oxidative stress
(Elsevier, 2016-01) Mahesh, R.
The prevalence of depression is about 2-3 times higher in diabetic patients compared to the general population, yet this comorbidity is poorly treated. This may partly be contributed to the inefficient pharmacotherapy. We evaluated if a novel 5HT3 receptor antagonist 4i (N-(3-Chloro-2-methylphenyl) quinoxalin-2-carboxamide), can prevent depression-like behavior associated with diabetes in mice. Also, the role of oxidative stress in antidepressant action of 4i was investigated.
5HT3 receptor antagonist (ondansetron) reverses depressive behavior evoked by chronic unpredictable stress in mice: Modulation of hypothalamic–pituitary–adrenocortical and brain serotonergic system
(Elsevier, 2014-09) Mahesh, R.
Chronic stress is one of the major causes of depression, associated with behavioral and biochemical impairments. 5HT3 receptor antagonists (such as ondansetron) have shown alleviation of depressive symptomology in preclinical and in few clinical studies. However, their effects in chronic stress-induced depressive behavior and the underlying mechanism(s) are yet to be known. In the present study, the effects of a 5HT3 receptor antagonist, ondansetron were evaluated in chronic unpredictable stress (CUS)-evoked depressive behavior. In addition, the possible mechanism was determined by measuring plasma corticosterone (CORT) as a marker of hypothalamic–pituitary–adrenocortical (HPA)-axis activity and serotonin levels in the discrete brain regions. Mice were subjected to a battery of unpredictable stressors for 28 days. Ondansetron (0.05, 0.1 and 1 mg/kg, p.o.) and fluoxetine (10 mg/kg, p.o.) were administered during the last 14 days (day 15–28th) of CUS testing paradigm. The results showed that the 4-week CUS produced significant depressive behavior in mice, which included increased despair effects in forced swim test (FST) and reward-related deficits in sucrose preference test. Biochemical assays demonstrated a significant increase in percentage of plasma CORT and decrease in percentage of serotonin levels in the discrete brain regions of CUS mice. Chronic ondansetron treatment, similar to that of positive control fluoxetine, significantly reversed despair effects in FST and reward-related deficits in sucrose preference test. In addition, ondansetron and fluoxetine treatments significantly increased percentage of serotonin levels in the measured brain regions and attenuated HPA-axis hyperactivity, as evidenced by low percentage of plasma CORT levels in CUS mice. These findings indicate the potential role of ondansetron (a 5HT3 receptor antagonist) in reversing CUS-induced depressive behavior, which is possibly mediated by its modulating effects on the HPA-axis and serotonergic system. Further, the study represents that 5HT3 receptor antagonists can be a potential therapeutic candidate for stress-related depressive disorders.
5HT3 receptors: Target for new antidepressant drugs
(Elsevier, 2016-05) Mahesh, R.
5HT3 receptors (5HT3Rs) have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3Rs produces antidepressant-like effects. However, the exact role of 5HT3Rs and the mode of antidepressant action of 5HT3R antagonists still remain a mystery. Here, we provide a comprehensive overview of 5HT3Rs: (a) regional and subcellular distribution of 5HT3Rs in discrete brain regions, (b) preclinical and clinical evidence supporting the antidepressant effect of 5HT3R antagonists, and (c) neurochemical, biological and neurocellular signaling pathways associated with the antidepressant action of 5HT3R antagonists. 5HT3Rs located on the serotonergic and other neurotransmitter interneuronal projections control their release and affect mood and emotional behavior; however, new evidence suggests that apart from modulating the neurotransmitter functions, 5HT3R antagonists have protective effects in the pathogenic events including hypothalamic–pituitary–adrenal-axis hyperactivity, brain oxidative stress and impaired neuronal plasticity, pointing to hereby unknown and novel mechanisms of their antidepressant action. Nonetheless, further investigations are warranted to establish the exact role of 5HT3Rs in depression and antidepressant action of 5HT3R antagonists.
Acetylcholine structure-based small activatable fluorogenic probe for specific detection of acetylcholinesterase
(ACS, 2023-05) Sidhu, Jagpreet Singh
Early detection of Alzheimer’s disease (AD) is important for taking proper measures against AD pathogenesis. Acetylcholinesterase (AChE) is widely reported to be associated with the pathogenicity of AD. Here, employing the “acetylcholine-mimic” approach, we designed and synthesized a new class of naphthalimide (Naph)-based fluorogenic probes for specific detection of AChE and avoiding interference of butyrylcholinesterase (BuChE), the pseudocholinesterase. We investigated the action of the probes on Electrophorus electricus AChE, and the native human brain AChE that we expressed in Escherichia coli and purified in the active form for the first time. The probe Naph-3 exhibited a substantial fluorescence enhancement with AChE and majorly avoided BuChE. Naph-3 successfully crossed the cell membrane of the Neuro-2a cells and fluoresced upon reaction with endogenous AChE. We further established that the probe could be effectively used for screening AChE inhibitors. Our study provides a new avenue for the specific detection of AChE, which can be extended to the diagnosis of AChE-related complications.
Acetylcholine Structure-Based Small Activatable Fluorogenic Probe for Specific Detection of Acetylcholinesterase
(ACS, 2023-05) Sidhu, Jagpreet Singh
Early detection of Alzheimer’s disease (AD) is important for taking proper measures against AD pathogenesis. Acetylcholinesterase (AChE) is widely reported to be associated with the pathogenicity of AD. Here, employing the “acetylcholine-mimic” approach, we designed and synthesized a new class of naphthalimide (Naph)-based fluorogenic probes for specific detection of AChE and avoiding interference of butyrylcholinesterase (BuChE), the pseudocholinesterase. We investigated the action of the probes on Electrophorus electricus AChE, and the native human brain AChE that we expressed in Escherichia coli and purified in the active form for the first time. The probe Naph-3 exhibited a substantial fluorescence enhancement with AChE and majorly avoided BuChE. Naph-3 successfully crossed the cell membrane of the Neuro-2a cells and fluoresced upon reaction with endogenous AChE. We further established that the probe could be effectively used for screening AChE inhibitors. Our study provides a new avenue for the specific detection of AChE, which can be extended to the diagnosis of AChE-related complications.
Acyl-coa synthetase long-chain isoenzymes in kidney diseases: mechanistic insights and therapeutic implications
(Wiley, 2024-08) Gaikwad, Anil Bhanudas
Long-chain acyl-CoA synthetases (ACSLs) are pivotal enzymes in fatty acid metabolism, essential for maintaining cellular homeostasis and energy production. Recent research has uncovered their significant involvement in the pathophysiology of various kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), and renal cell carcinoma (RCC). While ACSL1, ACSL3, ACSL4, and ACSL5 have been extensively studied for their roles in processes such as ferroptosis, lipid peroxidation, renal fibrosis, epithelial-mesenchymal transition, and tumor progression, the role of ACSL6 in kidney diseases remain largely unexplored. Notably, these isoenzymes exhibit distinct functions in different kidney diseases. Therefore, to provide a comprehensive understanding of their involvement, this review highlights the molecular pathways influenced by ACSLs and their roles in modulating cell death, inflammation, and fibrosis during kidney disease progression. By examining these mechanisms in detail, this review underscores the potential of ACSLs as biomarkers and therapeutic targets, advocating for further research to elucidate the precise roles of individual ACSL isoenzymes in kidney disease progression. Understanding these mechanisms opens new avenues for developing targeted interventions and improving therapeutic outcomes for patients with kidney diseases.
Additive manufacturing strategies for personalized drug delivery systems and medical devices
(Elsevier, 2024) Jain, Ankit
Medical additive manufacturing (MAM), 3D printing, or fused deposition modeling is considered a synonym for personalized medicines, digital pharmacy, or telemedicine. The concept is widely used to tailor more programmed, controlled, and modified drug-release profiles of drug delivery systems (DDS) with complex sizes and geometry. It is computer-aided manufacturing based on the layer-by-layer formation of designs and objects. The chapter includes not only their working principles, and processed materials, but their current progress potentials, industrial-scale applications, and challenges also. MAM is based on various new techniques such as inkjet printing, contour crafting (CC), stereolithography (SLA), powder bed fusion (PBF), direct energy deposition, fused deposition modeling (FDM), and pressure-assisted microsyringes (PAM) technology. In these techniques, thermoplastic polymers or hydrogel in sequential layers such as polyvinyl alcohol, polylactic acid, hydroxypropyl methylcellulose, Eudragit, chitosan, gelatin, polyvinylpyrrolidone (Kollidon), and poly(ε-caprolactone), etc., are used in the development of DDS. Future research could be organized with these advanced cost-effective printing techniques and compatible materials to widen the applications for 3D printing products and medical devices. The chapter encompasses a detailed account of materials, design, fabrication techniques, and applications of MAM in DDS and a special note on safe, efficient, and personalized medical devices
Advanced hydrogels in drug delivery and wound healing
(MDPI, 2024-12) Jain, Ankit
Advanced non-invasive diagnostic techniques for visualization and estimation of kidney fibrosis
(Elsevier, 2021-08) Gaikwad, Anil Bhanudas
Kidney fibrosis is marked by excessive extracellular matrix deposition during disease progression. Unfortunately, existing kidney function parameters do not predict the extent of kidney fibrosis. Moreover, the traditional histology methods for the assessment of kidney fibrosis require liquid and imaging biomarkers as well as needle-based biopsies, which are invasive and often associated with kidney injury. The repetitive analyses required to monitor the disease progression are therefore difficult. Hence, there is an unmet medical need for non-invasive and informative diagnostic approaches to monitor kidney fibrosis during the progression of chronic kidney disease. Here, we summarize the modern advances in diagnostic imaging techniques that have shown promise for non-invasive estimation of kidney fibrosis in pre-clinical and clinical studies.
Advanced Solid Oral Controlled-Release Formulations
(Elsevier, 2021) Singhvi, Gautam
Oral controlled release dosage forms have gained attention due to their numerous advantages that can overcome the limitations associated with conventional solid oral preparation to achieve the desired therapeutic efficacy. The pharmaceutical industry has extended patent lives through innovative repositioning and reformulation of existing drugs moieties. This has resulted in significant growth of the drug delivery market over the past few years. Advanced solid oral dosage forms belonging to the categories of gastro-retentive systems, pulsatile drug release, multiparticulate drug delivery systems, osmotic systems, colon-targeted systems, hydrodynamically balanced systems, and feedback-regulated drug delivery systems have been investigated extensively and have successfully hit the market. Patented technologies such as osmotic controlled-release oral delivery systems, liquid osmotic system, oral controlled absorption system, TIMERx, spheroidal oral drug absorption system, intestinal protective drug absorption system, and chronotherapeutic oral drug absorption system were also developed for targeting various parts of the gastrointestinal tract. This chapter discusses the factors influencing the fabrication of oral controlled formulations, mechanisms of drug release from oral controlled formulations, and their classification. With the upcoming automation in the pharma industry, ultra-long acting and 3D printing-based oral controlled preparation would be developed with better safety, efficacy, and lower cost, thereby benefitting the society at large.
Advancements in Polymeric Systems for Nucleic Acid Delivery
(CRC Press, 2018) Chitkara, Deepak; Mittal, Anupama
RNA interference (RNAi) has been suggested as a potential treatment method to improve current chemotherapeutic regimens. It is a sequence-specific, post-transcriptional gene silencing mechanism in animals and plants that targets mRNA encoded by the mutant gene. RNA-based strategies are useful in targeting the mutations that results in a gain of function wherein RNA levels are modified and includes the use of antisense oligonucleotide, triplex-forming oligonucleotides, aptamers, trans-splicing, segmental trans-splicing, ribozymes, DNAzymes, siRNA, and miRNA (Chitkara, Singh, & Mittal, 2016). Among these, siRNA and miRNA have generated a lot of interest as they could be easily synthesized, do not require genome integration, and thus could curtail potential problems of insertional mutagenesis. These are 20–25 base pair-long RNA oligonucleotides that are incorporated into the pre-RISC (RNA-induced
Advances in Antibody-Based Therapeutics for Cerebral Ischemia
(MDPI, 2022-12) Taliyan, Rajeev
Cerebral ischemia is an acute disorder characterized by an abrupt reduction in blood flow that results in immediate deprivation of both glucose and oxygen. The main types of cerebral ischemia are ischemic and hemorrhagic stroke. When a stroke occurs, several signaling pathways are activated, comprising necrosis, apoptosis, and autophagy as well as glial activation and white matter injury, which leads to neuronal cell death. Current treatments for strokes include challenging mechanical thrombectomy or tissue plasminogen activator, which increase the danger of cerebral bleeding, brain edema, and cerebral damage, limiting their usage in clinical settings. Monoclonal antibody therapy has proven to be effective and safe in the treatment of a variety of neurological disorders. In contrast, the evidence for stroke therapy is minimal. Recently, Clone MTS510 antibody targeting toll-like receptor-4 (TLR4) protein, ASC06-IgG1 antibody targeting acid sensing ion channel-1a (ASIC1a) protein, Anti-GluN1 antibodies targeting N-methyl-D-aspartate (NMDA) receptor associated calcium influx, GSK249320 antibody targeting myelin-associated glycoprotein (MAG), anti-High Mobility Group Box-1 antibody targeting high mobility group box-1 (HMGB1) are currently under clinical trials for cerebral ischemia treatment. In this article, we review the current antibody-based pharmaceuticals for neurological diseases, the use of antibody drugs in stroke, strategies to improve the efficacy of antibody therapeutics in cerebral ischemia, and the recent advancement of antibody drugs in clinical practice. Overall, we highlight the need of enhancing blood–brain barrier (BBB) penetration for the improvement of antibody-based therapeutics in the brain, which could greatly enhance the antibody medications for cerebral ischemia in clinical practice.
Advances in CRISPR-Cas systems for kidney diseases
(Elsevier, 2025) Gaikwad, Anil Bhanudas
Recent advances in CRISPR-Cas systems have revolutionised the study and treatment of kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and polycystic kidney disease (PKD). CRISPR-Cas technology offers precise and versatile tools for genetic modification in monogenic kidney disorders such as PKD and Alport syndrome. Recent advances in CRISPR technology have also shown promise in addressing other kidney diseases like AKI, CKD, and DKD. CRISPR-Cas holds promise to edit genetic mutations underlying these conditions, potentially leading to more effective and long-lasting treatments. Furthermore, the adaptability of CRISPR-Cas systems allows for developing tailored therapeutic strategies that specifically target the genetic and molecular mechanisms contributing to different kidney diseases. Beyond DNA modifications, CRISPR-Cas technologies also enable editing noncoding RNA, such as lncRNAs and miRNAs, in kidney diseases. Despite these advancements, significant challenges persist, including delivery efficiency to specific kidney cells and potential off-target effects. However, the rapid progress in CRISPR-Cas technology suggests a transformative impact on the future management of kidney diseases, offering the potential for enhanced patient outcomes through personalised and precise therapeutic approaches. This chapter highlights the recent advancement of CRISPR-Cas systems and their potential applications in various kidney diseases.