Pharmaceutical Sciences and Natural Products - Research Publications
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Item Design, Synthesis and Evaluation of Donepezil-Rasagiline Based Compounds as Multipotent Inhibitors for the Treatment of Alzheimer’s Disease(Central University of Punjab, 2019) Kumar, Bhupinder; Kumar, VinodAlzheimer’s disease (AD) is multifactorial in nature and different enzymes including MAO, AChE, and amyloid beta are implicated in its pathogenesis. The pathomechanism of AD is complex in nature and single target drugs proved to be ineffective for the treatment of the disease. With an aim of developing dual/multipotent inhibitors, 4,6- diphenylpyrimidines were optionally substituted with propargyl group and an ethyl chain containing a cyclic or acyclic tertiary nitrogen atom (piperidine/morpholine/pyrrolidine/N,N-dimethyl) as potential pharmacophores for MAO and AChE enzymes. Compound VB1 was found to be the most potent MAO-A (IC50 value of 18.34 ± 0.38 nM) inhibitor and VB8 was found to be the most potent AChE (IC50 value of 9.54 ± 0.07 nM) inhibitor. Compound VB3 was another promising compound in series-I with IC50 values of 28.33 ± 3.22 nM and 18.92 ± 0.29 nM against MAO-A and AChE, respectively and displayed very high selectivity index (103) for AChE over BuChE. These compounds were found to be reversible inhibitors of MAO and AChE enzymes and non-toxic to the human neuroblastoma SH-SY5Y cells. Based on structure-activity relationship analysis of the first series of compounds, second series of the compounds were designed by fixing the position of piperidine/morpholine ethyl chain at the para position of one of the phenyl rings. In the second series, compound VP15 v was found to be a multi-potent inhibitor of MAO-B and AChE with IC50 values of 0.37 ± 0.03 μM and 0.04 ± 0.003 μM, respectively. VP15 was found to be selective for MAOB with selectivity index of 270 over MAO-A. It also displayed SI of 625 for AChE over BuChE. VP15 was found to be irreversible inhibitor of MAO-B. In the third series of target compounds, both the phenyl rings of diphenylpyrimidines were substituted with O-propargyl groups. Different derivatives have been synthesized with O-propargyl groups substituted at ortho, meta and para positions of the phenyl rings. In the third series of compounds, AVB1 and AVB4 were found to be the most potent inhibitors of AChE and MAO-B with IC50 values of 1.35 ±0.03 μM and 1.49 ± 0.09 μM, respectively. In the reversible inhibition studies, the lead compounds were found to be reversible inhibitors of MAO-B and AChE enzymes. In the ROS protection inhibition studies, AVB1 and AVB4 displayed good activity in SH-SY5Y cells and AVB1 reduced the ROS levels up to 30% at 5 μM. This series of compounds were also found to be non-toxic to the SH-SY5Y cells in the cytotoxicity studies. Thus, from the present study it can be concluded that 4,6-diphenylpyrimidine derivatives can act as potential lead for the development of effective drug candidates for the treatment of AD. Compound VB3 and VP15 were found to be the most potent dual inhibitors of MAO and AChE.Item Protective Effect of Hemin Against Experimental Chronic Fatigue Syndrome in Mice: Possible Role of Neurotransmitters(Springer, 2020) Thakur, V; Jamwal, S; Kumar, M; Rahi, V; Kumar, P.Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and relapsing fatigue along with long-lasting and debilitating fatigue, myalgia, cognitive impairment, and many other common symptoms. The present study was conducted to explore the protective effect of hemin on CFS in experimental mice. Male albino mice were subjected to stress-induced CFS in a forced swimming test apparatus for 21 days. After animals had been subjected to the forced swimming test, hemin (5 and 10 mg/kg; i.p.) and hemin (10 mg/kg) + tin(IV) protoporphyrin (SnPP), a hemeoxygenase-1 (HO-1) enzyme inhibitor, were administered daily for 21 days. Various behavioral tests (immobility period, locomotor activity, grip strength, and anxiety) and estimations of biochemical parameters (lipid peroxidation, nitrite, and GSH), mitochondrial complex dysfunctions (complexes I and II), and neurotransmitters (dopamine, serotonin, and norepinephrine and their metabolites) were subsequently assessed. Animals exposed to 10 min of forced swimming session for 21 days showed a fatigue-like behavior (as increase in immobility period, decreased grip strength, and anxiety) and biochemical alteration observed by increased oxidative stress, mitochondrial dysfunction, and neurotransmitter level alteration. Treatment with hemin (5 and 10 mg/kg) for 21 days significantly improved the decreased immobility period, increased locomotor activity, and improved anxiety-like behavior, oxidative defense, mitochondrial complex dysfunction, and neurotransmitter level in the brain. Further, these observations were reversed by SnPP, suggesting that the antifatigue effect of hemin is HO-1 dependent. The present study highlights the protective role of hemin against experimental CFS-induced behavioral, biochemical, and neurotransmitter alterations. - 2020, Springer Science+Business Media, LLC, part of Springer Nature.Item Tetrazoles as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies(Elsevier, 2020) Dhiman, N; Kaur, K; Jaitak, VikasCancer is a leading cause of death worldwide. Even after the availability of numerous drugs and treatments in the market, scientists and researchers are focusing on new therapies because of their resistance and toxicity issues. The newly synthesized drug candidates are able to demonstrate in vitro activity but are unable to reach clinical trials due to their rapid metabolism and low bioavailability. Therefore there is an imperative requisite to expand novel anticancer negotiators with tremendous activity as well as in vivo efficacy. Tetrazole is a promising pharmacophore which is metabolically more stable and acts as a bioisosteric analogue for many functional groups. Tetrazole fragment is often castoff with other pharmacophores in the expansion of novel anticancer drugs. This is the first systematic review that emphasizes on contemporary strategies used for the inclusion of tetrazole moiety, mechanistic targets along with comprehensive structural activity relationship studies to provide perspective into the rational design of high-efficiency tetrazole-based anticancer drug candidates. - 2020 Elsevier LtdItem Global trends in pesticides: A looming threat and viable alternatives(Academic Press, 2020) Sharma, A; Shukla, A; Attri, K; Kumar, M; Kumar, P; Suttee, A; Singh, G; Barnwal, R.P; Singla, N.Pesticides are widely used chemical compounds in agriculture to destroy insects, pests and weeds. In modern era, they form an indispensable part of agricultural and health practices. Globally, nearly 3 billion kg of pesticides are used every year with a budget of ~40 billion USD. This extensive usage has increased the crop yield as well as led to significant reduction in harvest losses and thereby, enhanced food availability. On the other hand, indiscriminate usage of these chemicals has led to several environmental implications and caused adverse effects on human health. Epidemiological evidences have revealed the harmful effects of pesticides exposure on various organs including liver, brain, lungs and colon. Recent investigations have shown that pesticides can also lead to fatal consequences such as cancer among individuals. These chemicals enter ecosystem, thus hampering the sensitive environmental equilibrium through bio-accumulation. Due to their non-biodegradable nature, they can persist in nature for years and are regarded as potent biohazard. Worldwide, very few surveillance methods have been considered, which can bring awareness among the individuals, therefore the present review is an attempt to delineate consequences induced by various types of pesticide exposure on the environment. Further, the prospective of biopesticides use could facilitate the increase of crop production without compromising human health.- 2020 Elsevier Inc.Item Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab(Springer, 2019) Singla, H; Kaur, R.P; Shafi, G; Vashistha, R; Banipal, R.P.S; Kumar, Vinod; Munshi, AnjanaHuman epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA. © 2018, Springer Nature B.V.Item 4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease(American Chemical Society, 2019) Kumar, B; Dwivedi, A.R; Sarkar, B; Gupta, S.K; Krishnamurthy, S; Mantha, Anil K; Parkash, Jyoti; Kumar, VinodAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC 50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with an IC 50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC 50 value of 9.54 ± 0.07 nM and displayed an IC 50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H 2 O 2 -induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease. © 2018 American Chemical Society.Item Stevia rebaudiana targeting α-amylase: An in-vitro and in-silico mechanistic study(Taylor and Francis, 2019) Singla, R; Singla, N; Jaitak, VikasDiabetes mellitus (DM) is the fastest growing metabolic disorder in the world. Recently, more attention is paid to the study of natural products due to side effects of synthetic drugs. Stevia rebaudiana (Bertoni) is considered an encouraging starting point for the antidiabetic lead development. In the present study, the in vitro α-amylase inhibitory activity of the extracts of S. rebaudiana is investigated. In order to understand the molecular mechanism and future pharmacophore development, in silico study of secondary metabolites isolated from S. rebaudiana was carried out. Results indicated that water extract shows highest α-amylase inhibitory activity as compared to other extracts. Moreover, compound 20 (rebaudioside A) which has been previously reported and isolated from water extract showed the impressive binding profile with α-amylase. Therefore, our study suggests that S. rebaudiana could be used in the development of therapeutic drugs for the treatment of diabetes. © 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group.Item Knoevenagel/tandem knoevenagel and michael adducts of cyclohexane-1,3-dione and aryl aldehydes: Synthesis, DFT studies, xanthine oxidase inhibitory potential, and molecular modeling(American Chemical Society, 2019) Arora, S; Joshi, G; Kalra, S; Wani, A.A; Bharatam, P.V; Kumar, Pradeep; Kumar, RajXanthine oxidase (XO) plays a crucial role in the formation of uric acid by oxidative hydroxylation of purines. Herein, we report the design and synthesis of Knoevenagel/tandem Knoevenagel and Michael adducts of cyclohexane-1,3-dione and aryl aldehydes as nonpurine XO inhibitors derived from naturally occurring scaffolds. Density functional theory calculations highlighted the reaction pathways and reasoned the formation of tandem Knoevenagel and Michael adducts. The synthetics were assessed for their XO inhibitory potential, and among them, four compounds (1b, 1g, 2b, and 3a) were found to possess best IC 50 values in the range of 3.66-4.98 μM. Interestingly, Knoevenagel adducts exhibited a competitive-type inhibition, whereas tandem Knoevenagel and Michael adducts produced a noncompetitive mode of inhibition. The compounds were capable of reducing the H 2 O 2 levels induced by XO, both in normal and cancer cells with no significant cytotoxicity. Molecular modeling studies highlighted the role of interactions of compounds with residual amino acids of the XO active site and also corroborated with the observed structure-activity relationship. © 2019 American Chemical Society.Item Pd-Catalyzed Four-Component Sequential Reaction Delivers a Modular Fluorophore Platform for Cell Imaging(American Chemical Society, 2019) Ansari, A.J; Joshi, G; Sharma, P; Maurya, A.K; Metre, R.K; Agnihotri, V.K; Chandaluri, C.G; Kumar, Raj; Singh, S; Sawant, D.M.A Pd-catalyzed cascade reaction of four versatile privileged synthons is described. The sequential reaction involves the formation of five new chemical bonds by concatenating three distinct chemical steps. One of the derivatives exhibited absorption in the visible region, fluorescence with a high quantum yield, and excellent photostability. Its application is explored in live cell imaging, which exhibited cytoplasmic and mitochondrial specific staining with no toxicity. © 2019 American Chemical Society.Item Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase(Elsevier, 2019) Kumar, Bhupinder; Kumar, V; Prashar, V; Saini, S; Dwivedi, A.R; Bajaj, B; Mehta, D; Parkash, Jyoti; Kumar, VinodAlzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 ± 0.09 μM and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 1.35 ± 0.03 μM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug. © 2019