Publications by authors named "Ozair Alam"

45 Publications

Sirolimus loaded chitosan functionalized poly (lactic-co-glycolic acid) (PLGA) nanoparticles for potential treatment of age-related macular degeneration.

Int J Biol Macromol 2021 Sep 16;191:548-559. Epub 2021 Sep 16.

Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi 110062, India. Electronic address:

The usefulness of sirolimus (SIR) in the treatment of diseases that involve retinal degeneration like age-related macular degeneration (AMD) has been well documented. However, the problem still remains probably owing to the peculiar environment of the eye and/or unfavourable physiochemical profile of SIR. In the present work, we aimed to fabricate sirolimus loaded PLGA nanoparticles (SIR-PLGA-NP) and chitosan decorated PLGA nanoparticles (SIR-CH-PLGA-NP) to be administered via non-invasive subconjunctival route. Both the nanoparticles were characterized in terms of size, zeta potential, DSC, FTIR and XRD analysis. Quality by Design (QbD) approach was employed during the preparation of nanoparticles and the presence of chitosan coating was confirmed through thermogravimetric analysis and contact angle studies. Cationic polymer modification showed sustained in-vitro SIR release and enhanced ex-vivo scleral permeation and penetration. Further, SIR-CH-PLGA-NP revealed enhanced cellular uptake and thus, reduced lipopolysaccharide (LPS)-induced free-radicals generation by RAW 264.7 cells. The prepared nanoparticles were devoid of residual solvent and were found to be safe in HET-CAM analysis, RBCs damage analysis and histopathology studies. Moreover, high anti-angiogenic potential was observed in SIR-CH-PLGA-NP compared with SIR-PLGA-NP in chorioallantoic membrane (CAM) test. Overall, the current work opens up an avenue for further investigation of CH-PLGA-NP as SIR nanocarrier in the treatment of AMD.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.09.069DOI Listing
September 2021

Current status of novel pyridine fused derivatives as anticancer agents: An insight into future perspectives and structure activity relationship (SAR).

Curr Top Med Chem 2021 Sep 16. Epub 2021 Sep 16.

Department of Chemistry, School of Chemical and Life sciences, Jamia Hamdard, New Delhi-110062. India.

Cancer is a heterogeneous disease characterized by an abnormal and uncontrolled division of the cells leading to tumors that invade the adjacent normal tissues. After cardiovascular diseases, it is the second most prevalent disease accounting for one in every six deaths worldwide. This alarming rate thus, demands an urgent need to investigate more effective drugs to combat the said disease. Oxygen and nitrogen-based heterocyclic compounds have shown remarkable therapeutic activity towards several diseases, including cancer. In this review, we have attempted to summarize the work done in the last decade (2009-2019), highlighting the anticancer activity of pyrido fused five-membered heterocyclic ring derivatives. Additionally, we have focused on seven heterocyclic pyridine fused rings: Imidazopyridine, Triazolopyridine, Pyrrolopyridine, Pyrazolopyridines, Thienopyridine, and Isoxazolopyridine. A total of forty-nine compounds have been studied based on their in-vitro cytotoxic activity and their structure-activity relationship, underlining the anticancer activity of their various pharmacophores and substituents. This review, therefore, aims to draw the attention of the researchers worldwide towards the enormous scope of development of heterocyclic drug compounds, focussing mainly on pyrido fused five-membered heterocyclic rings as anticancer drugs.
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http://dx.doi.org/10.2174/1568026621666210916171015DOI Listing
September 2021

Antitumor and hepatoprotective effect of Cuscuta reflexa Roxb. in a murine model of colon cancer.

J Ethnopharmacol 2022 Jan 4;282:114597. Epub 2021 Sep 4.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India. Electronic address:

Ethnopharmacological Relevance: Cuscuta reflexa Roxb. (C. reflexa) is a well-known traditional herbal plant, with numerous inherent therapeutic potentials including anticancer, antitumor, antibacterial, analgesic, anthelmintic, laxative and others. Moreover, the anticancer and antitumor potentials of this herb are ongoing with several trails, thus an attempt was made to assess the anticancer and hepatoprotective potentials of traditional C. reflexa herbs.

Method: The dried ethanolic extract of C. reflexa was tested for acute oral toxicity in the treated animals subsequently their behavioral, neurological, and autonomic profiles changes were observed. The preliminary anti-cancer effects of extracts against 1, 2- Dimethyl hydrazine (DMH) induced animals were assessed through barium enema X-ray, colonoscopy, and Aberrant crypt foci (ACF) studies. The blood samples of the animals (treated and untreated) were collected and their in-vitro histological parameters were evaluated by the experienced technician.

Results: It was observed that C. reflexa significantly reduced Disease activity indexing (DAI) level and ACF counting, as well as demonstrated similar activity as of the standard drug 5-Fluorouracil (5-FU). Histopathological results revealed that the apoptotic bodies decreased in the DMH-induced group (group II) during cancer progression while in 5-FU treated (group III) and C. reflexa treated (group IV and V) animals the apoptotic bodies were increased. Inversely, the mitotic bodies increased in group II animals and reduced in group III, IV, and V animals. In the colonic section, DMH-induced cancer assay exhibited significant effects on the levels of hemoglobin, Packed cell volume (PCV), Red blood cell (RBC) counts, Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular volume (MCV), and Mean cell hemoglobin (MCH), and was found to be less in group II animals whereas administration of C. reflexa efficiently recovered back the loss probably by healing the colon damage/depletion of cancer progression. Moreover, compared to the group II animals, the neutrophil count was within the normal range in C. reflexa administered group.

Conclusions: In the present study, the major hematological parameters significantly increased within DMH treated animals and exhibited extensive damage in the hepatic regions. Moreover, the histopathological findings demonstrated that the C. reflexa extracts potentially reduced the cell proliferation, with no toxicity. The C. reflexa extracts exhibited impending anti-cancer activity as well as protected the hepatic cells and thus could be potentially used in the management of colon or colorectal cancer and hepatic impairments.
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http://dx.doi.org/10.1016/j.jep.2021.114597DOI Listing
January 2022

Innovations and Patent Trends in the Development of USFDA Approved Protein Kinase Inhibitors in the Last Two Decades.

Pharmaceuticals (Basel) 2021 Jul 22;14(8). Epub 2021 Jul 22.

Department of Chemistry, College of Science and Humanities, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.

Protein kinase inhibitors (PKIs) are important therapeutic agents. As of 31 May 2021, the United States Food and Drug Administration (USFDA) has approved 70 PKIs. Most of the PKIs are employed to treat cancer and inflammatory diseases. Imatinib was the first PKI approved by USFDA in 2001. This review summarizes the compound patents and the essential polymorph patents of the PKIs approved by the USFDA from 2001 to 31 May 2021. The dates on the generic drug availability of the PKIs in the USA market have also been forecasted. It is expected that 19 and 48 PKIs will be genericized by 2025 and 2030, respectively, due to their compound patent expiry. This may reduce the financial toxicity associated with the existing PKIs. There are nearly 535 reported PKs. However, the USFDA approved PKIs target only about 10-15% of the total said PKs. As a result, there are still a large number of unexplored PKs. As the field advances during the next 20 years, one can anticipate that PKIs with many scaffolds, chemotypes, and pharmacophores will be developed.
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http://dx.doi.org/10.3390/ph14080710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400070PMC
July 2021

Neuroprotective Effect of Fisetin Through Suppression of IL-1R/TLR Axis and Apoptosis in Pentylenetetrazole-Induced Kindling in Mice.

Front Neurol 2021 21;12:689069. Epub 2021 Jul 21.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

Epilepsy is a complex neurological disorder, characterized by frequent electrical activity in brain regions. Inflammation and apoptosis cascade activation are serious neurological sequelae during seizures. Fisetin (3, 3',4',7-tetrahydroxyflavone), a flavonoid molecule, is considered for its effective anti-inflammatory and anti-apoptotic properties. This study investigated the neuroprotective effect of fisetin on experimental epilepsy. For acute studies, increasing current electroshock (ICES) and pentylenetetrazole (PTZ)-induced seizure tests were performed to evaluate the antiseizure activity of fisetin. For the chronic study, the kindling model was established by the administration of PTZ in subconvulsive dose (25 mg/kg, i.p.). Mice were treated with fisetin (5, 10, and 20 mg/kg, p.o.) to study its probable antiseizure mechanism. The kindled mice were evaluated for seizure scores. Their hippocampus and cortex were assessed for neuronal damage, inflammation, and apoptosis. Histological alterations were observed in the hippocampus of the experimental mice. Levels of high mobility group box 1 (HMGB1), Toll-like receptor-4 (TLR-4), interleukin-1 receptor 1 (IL-1R1), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed in the hippocampus and cortex by ELISA. The immunoreactivity and mRNA expressions of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), cytochrome C, and caspase-3 were quantified by immunohistochemical analysis and real-time PCR. Phosphorylation ELISA was performed to evaluate AkT/mTOR (mammalian target of rapamycin) activation in the hippocampus and cortex of the kindled mice. The results showed that fisetin administration increased the seizure threshold current (STC) in the ICES test. In PTZ-induced seizures, fisetin administration increased the latency for myoclonic jerks (MJs) and generalized seizures (GSs). In the PTZ-induced kindling model, fisetin administration dose-dependently suppressed the development of kindling and the associated neuronal damage in the experimental mice. Further, fisetin administration ameliorated kindling-induced neuroinflammation as evident from decreased levels of HMGB1, TLR-4, IL-1R1, IL-1β, IL-6, and TNF-α in the hippocampus and cortex of the kindled mice. Also, the immunoreactivity and mRNA expressions of inflammatory molecules, NF-κB, and COX-2 were decreased with fisetin administration in the kindled animals. Decreased phosphorylation of the AkT/mTOR pathway was reported with fisetin administration in the hippocampus and cortex of the kindled mice. The immunoreactivity and mRNA expressions of apoptotic molecules, cytochrome C, and caspase-3 were attenuated upon fisetin administration. The findings suggest that fisetin shows a neuroprotective effect by suppressing the release of inflammatory and apoptosis molecules and attenuating histological alterations during experimental epilepsy.
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http://dx.doi.org/10.3389/fneur.2021.689069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333701PMC
July 2021

Development of a Validated Bioanalytical UPLC-MS/MS Method for Quantification of Neratinib: A Recent Application to Pharmacokinetic Studies in Rat Plasma.

J Chromatogr Sci 2021 Jul 6. Epub 2021 Jul 6.

Department of Pharmaceutical Sciences, Shalom Institute of Health & Allied Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Allahabad 110062, India.

Neratinib, a tyrosine kinase inhibitor, was very recently approved by USFDA in 2017 as an anticancer drug to treat of HER2 positive breast cancers. The present work provides an account on the development of a validated bioanalytical UPLC-MS/MS method for quantification of neratinib and internal standard (imatinib) in rat plasma and tissue homogenates. A UPLC having a 100 mm C18 column (1.7 μm sized particles) was used with acetonitrile (0.1% formic acid): 2 mMol of ammonium acetate in water (pH 3.5) as the mobile phase. An efficient chromatographic separation was performed and detection was achieved by monitoring precursor-to-product ion transitions with m/z 557.29 → 112.06 for neratinib and m/z 494.43 → 294.17 for IS. The method demonstrated excellent linearity in the spiked plasma drug concentrating ranging between 1 and 800 ng.mL-1 (r2 = 0999), with lower limit of quantification (LLOQ) was observed at 1 ng.mL-1. Intra-assay and inter-assay precision relative standard deviations were found to be within 6.58. Mean extraction recovery for neratinib and IS were 99.44 and 99.33%, while matrix effect for neratinib and IS was ranging between -4.35 and - 3.66%, respectively. Overall, the method showed successful applicability in pharmacokinetic analysis of pure various formulations in Wistar rat plasma.
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http://dx.doi.org/10.1093/chromsci/bmab089DOI Listing
July 2021

GPR119 agonists: Novel therapeutic agents for type 2 diabetes mellitus.

Bioorg Chem 2021 08 19;113:104998. Epub 2021 May 19.

Department of Chemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi-110062, India.

Diabetes mellitus type 2 (T2D) is a group of genetically heterogeneous metabolic disorders whose frequency has gradually risen worldwide. Diabetes mellitus Type 2 (T2D) has started to achieve a pandemic level, and it is estimated that within the next decade, cases of diabetes might get double due to increase in aging population. Diabetes is rightly called the 'silent killer' because it has emerged to be one of the major causes, leading to renal failure, loss of vision; besides cardiac arrest in India. Thus, a clinical requirement for the oral drug molecules monitoring glucose homeostasis appears to be unmet. GPR119 agonist, a family of G-protein coupled receptors, usually noticed in β-cells of pancreatic as well as intestinal L cells, drew considerable interest for type 2 diabetes mellitus (T2D). GPR119 monitors physiological mechanisms that enhance homeostasis of glucose, such as glucose-like peptide-1, gastrointestinal incretin hormone levels, pancreatic beta cell-dependent insulin secretion and glucose-dependent insulinotropic peptide (GIP). In this manuscript, we have reviewed the work done in the last five years (2015-2020) which gives an approach to design, synthesize, evaluate and study the structural activity relationship of novel GPR119 agonist-based lead compounds. Our article would help the researchers and guide their endeavours in the direction of strategy and development of innovative, effective GPR119 agonist-based compounds for the management of diabetes mellitus type 2.
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http://dx.doi.org/10.1016/j.bioorg.2021.104998DOI Listing
August 2021

An analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α.

J Biomol Struct Dyn 2020 Nov 2:1-14. Epub 2020 Nov 2.

Department of Pharmaceutical Chemistry & Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Saudi Arabia.

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing -5.30 kcal/mol and -84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting -6.9 kcal/mol and -66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs.
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http://dx.doi.org/10.1080/07391102.2020.1841028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643422PMC
November 2020

Effect of augmented glycation in mobilization of plasma free fatty acids in type 2 diabetes mellitus.

Diabetes Metab Syndr 2020 Sep - Oct;14(5):1385-1389. Epub 2020 Jul 18.

Department of Biochemistry, HIMSR, Jamia Hamdard, New Delhi, India. Electronic address:

Background And Aims: Type 2 Diabetes Mellitus (T2DM) is known to be associated with an increase in total plasma free fatty acid (FFA) concentration. The present study was conducted to determine the changes in plasma fatty acids at different levels of glycation in type 2 diabetes mellitus.

Methods: The study involved 50 subjects having different levels of glycation (HbA1c 4.9-15.0%) and further categorized in 5 groups [group 1 (HbA1c <6%), group 2 (HbA1c 6-7%), group 3 (HbA1c 7.1-9%), group 4 (HbA1c (9.1-12%) and group 5 (HbA1c >12%)] with 10 subjects in each group.

Results: A total of 19 free fatty acids were detected by gas chromatography-mass spectrometry (GC-MS) analysis in the plasma samples. The levels of lauric acid (C12:0) and stearic acid (C18:0) were significantly raised at an advanced stage of glycation (HbA1c 9.1-15%). Long-chain fatty acids, pentadecanoic acid (C15:0) and palmitic acid (C16:0) levels were elevated in hyperglycemia as compared to normoglycaemic subjects (HbA1c <6%). Moreover, levels of mono and polyunsaturated fatty acids, oleic acid (C18:1) and linoleic acid (C18:2, w6) were significantly decreased in patients with increased levels of glycation (HbA1c 6-15%).

Conclusion: GC-MS is a novel way to study the plasma fatty acid profiling and findings of this study suggest that monitoring alterations in plasma FFA profile may be of prognostic value.
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http://dx.doi.org/10.1016/j.dsx.2020.07.028DOI Listing
July 2021

Novel quinazoline-based EGFR kinase inhibitors: A review focussing on SAR and molecular docking studies (2015-2019).

Eur J Med Chem 2020 Oct 22;204:112640. Epub 2020 Jul 22.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha, Pin Code 91911, Saudi Arabia.

The over expression of EGFR has been recognized as the driver mechanism in the occurrence and progression of carcinomas such as lung cancer, breast cancer, pancreatic cancer, etcetera. EGFR receptor was thus established as an important target for the management of solid tumors. The occurrence of resistance caused as a result of mutations in EGFR has presented a formidable challenge in the discovery of novel inhibitors of EGFR. This has resulted in the development of three generations of EGFR TKIs. Newer mutations like C797S cause failure of Osimertinib and other EGFR TKIs belonging to the third-generation caused by the development of resistance. In this review, we have summarized the work done in the last five years to overcome the limitations of currently marketed drugs, giving structural activity relationships of quinazoline-based lead compounds synthesized and tested recently. We have also highlighted the shortcomings of the currently used approaches and have provided guidance for circumventing these limitations. Our review would help medicinal chemists streamline and guide their efforts towards developing novel quinazoline-based EGFR inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2020.112640DOI Listing
October 2020

Recent advancement in the discovery and development of anti-epileptic biomolecules: An insight into structure activity relationship and Docking.

Eur J Pharm Sci 2020 Oct 28;153:105494. Epub 2020 Jul 28.

Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.

Although there have been many advancements in scientific research and development, the cause of epilepsy still remains an open challenge. In spite of high throughput research in the field of anti-epileptic drugs, efficacy void is still prevalent before the researchers. Researchers have persistently been exploring all the possibilities to curb undesirable side effects of the anti-epileptic drugs or looking for a more substantial approach to diminish or cure epilepsy. The drug development has shown a hope to medicinal chemists and researchers to carry further research by going through a substantial literature survey. This review article attempts to describe the recent developments in the anti-epileptic agents, pertaining to different molecular scaffolds considering their structure-activity relationship, docking studies and their mechanism of actions.
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http://dx.doi.org/10.1016/j.ejps.2020.105494DOI Listing
October 2020

Design, Synthesis, Molecular Docking, and Anticancer Evaluation of Pyrazole Linked Pyrazoline Derivatives with Carbothioamide Tail as EGFR Kinase Inhibitors.

Anticancer Agents Med Chem 2021 ;21(1):42-60

Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi-110062, India.

Background: The Epidermal Growth Factor Receptor (known as EGFR) induces cell differentiation and proliferation upon activation through the binding of its ligands. Since EGFR is thought to be involved in the development of cancer, the identification of new target inhibitors is the most viable approach, which recently gained momentum as a potential anticancer therapy.

Objective: To assess various pyrazole linked pyrazoline derivatives with carbothioamide for EGFR kinase inhibitory as well as anti-proliferative activity against human cancer cell lines viz. A549 (non-small cell lung tumor), MCF-7 (breast cancer cell line), SiHa (cancerous tissues of the cervix uteri), and HCT-116 (colon cancer cell line).

Methods: In vitro EGFR kinase assay, in vitro MTT assay, Lactate dehydrogenase release, nuclear staining (DAPI), and flow cytometry cell analysis.

Results: Compounds 6h and 6j inhibited EGFR kinase at concentrations of 1.66μM and 1.9μM, respectively. Furthermore, compounds 6h and 6j showed the most potent anti-proliferative results against the A549 KRAS mutation cell line (IC50 = 9.3 & 10.2μM). Through DAPI staining and phase contrast microscopy, it was established that compounds 6h and 6j also induced apoptotic activity in A549 cells. This activity was further confirmed by FACS using Annexin-V-FITC and Propidium Iodide (PI) labeling. Molecular docking studies performed on 6h and 6j suggested that the compounds can bind to the hinge region of ATP binding site of EGFR tyrosine kinase in a similar pose as that of the standard drug gefitinib.

Conclusion: The potential anticancer activity of compounds 6h and 6j was confirmed and need further exploration in cancer cell lines of different tissue origin and signaling pathways, as well as in animal models of cancer development.
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http://dx.doi.org/10.2174/1871520620666200727093613DOI Listing
June 2021

Development and validation of a high throughput bioanalytical UPLC-MS/MS method for simultaneous determination of tamoxifen and sulphoraphane in rat plasma: Application to an oral pharmacokinetic study.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Sep 6;1152:122260. Epub 2020 Jul 6.

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. Electronic address:

Tamoxifen (TAM) is the choice of a drug approved by the Food and Drug Administration (FDA) for the treatment of estrogen-positive receptor (ER+) breast cancer. Sulphoraphane (SFN), a natural plant antioxidant compound, also acts on estrogen-positive breast cancer receptor. Thus, a combination of TAM with SFN is preferred as it helps to minimize the drug-related toxicity and increases the therapeutic efficacy by providing synergistic anticancer effects of both drugs. In the present study, a new simple, sensitive, precise, and selective UPLC-MS/MS method was developed for the simultaneous quantification of tamoxifen and sulphoraphane using propranolol as an internal standard (IS) in rat plasma. Chromatographic separation was achieved on reverse phase Acquity UPLC BEH C column (50 mm × 2.1 mm, i.d., 1.7 μm) with an isocratic mobile phase composed of solvent A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in water) (80:20, v/v) at a flow-rate of 0.4 mL/min. The detection and quantification of analytes was performed on Waters Zspray Xevo TQD using selected-ion monitoring operated under a positive electrospray ionization mode. The transitions were m/z = 372.0 [M+H] → 71.92 for tamoxifen, m/z = 177.9 [M+H] → 113.9 for sulphoraphane and m/z = 260.3 [M+H] → 116.1 for propranolol. The method was linear over the concentration range of 8-500 ng/mL (r = 0.9996) for tamoxifen, 30-2000 ng/mL (r = 0.9998) for sulphoraphane with insignificant matrix effect and high extraction recovery on spiked quality control (QC) samples. The intra- and inter-batch precisions and accuracy were within the acceptable limits, and both the analytes were found to be stable throughout the short term, long term and freeze thaw stability studies. The validated method was successfully applied for the simultaneous estimation of TAM and SFN in an oral pharmacokinetic study in female Wistar rats. This developed UPLC-MS/MS method could be a valuable tool for future pharmacokinetic interaction, therapeutic drug monitoring and pharmacokinetic characterization of novel formulations.
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http://dx.doi.org/10.1016/j.jchromb.2020.122260DOI Listing
September 2020

Design, synthesis, and biological evaluation of imidazopyridine-linked thiazolidinone as potential anticancer agents.

Arch Pharm (Weinheim) 2020 Oct 6;353(10):e2000071. Epub 2020 Jul 6.

Department of Pharmaceutics, School of Medical and Allied Sciences, Galgotias University, Greater Noida, India.

In this study, two series of imidazopyridine-linked thiazolidinone rings (5a-h and 6a-h) constituting 16 new compounds were synthesized and tested for their antiproliferative activity against a panel of three human cancer cell lines, that is, MCF-7 (human breast cancer), A549 (human lung cancer), and DU145 (human prostate cancer). Three compounds, 5h, 6f, and 6h, exhibited remarkable results against all three cell lines, but compound 6h was found to be the most active one against the breast cancer cell line. Among all the synthesized compounds, 6h displayed the highest antioxidant results. Furthermore, the potent compounds 5h, 6f, and 6h showed no signs of toxicity at doses ranging from 50 to 500 mg/kg of animal body weight. The biochemical parameters (SGOT and SGPT) of compound 6h nearly matched the control in hepatotoxicity studies. The molecular docking and MM-GBSADG binding studies are in agreement with the in vitro anticancer and antioxidant activity results. The most promising compound 6h was found to have the highest docking score and binding energy, and its absorption, distribution, metabolism, and excretion (ADME) parameters are in the acceptable range. Thus, it can be concluded that 6h, an imidazopyridine derivative endowed with a thiazolidinone ring system, has the potential to be developed as an anticancer agent.
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http://dx.doi.org/10.1002/ardp.202000071DOI Listing
October 2020

Recent progress of 1,3,4-oxadiazoles as anticonvulsants: Future horizons.

Arch Pharm (Weinheim) 2020 Jul 21;353(7):e1900342. Epub 2020 Apr 21.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (Formerly Faculty of Pharmacy), Jamia Hamdard, Hamdard Nagar, New Delhi, India.

Epilepsy is the most common neurological disorder, which affects more than 50 million people worldwide. Despite the development and use of several antiepileptic drugs (AEDs), attempted seizure control fails in almost 30% of the individuals treated. Other patients benefit from seizure control by drug therapy at the expense of dose-related toxicity and side effects. These drawbacks with conventional AEDs demand the need for developing more effective and safer antiseizure agents. As a result, extensive efforts are devoted to design and develop new effective molecules as antiepileptics. This area of research to find more effective and safer AEDs is important and challenging. This review describes the future perspective of various 1,3,4-oxadiazole derivatives as anticonvulsant agents and focuses on the design and development of the new effective molecule.
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http://dx.doi.org/10.1002/ardp.201900342DOI Listing
July 2020

Lipid-based nanoformulations in the treatment of neurological disorders.

Drug Metab Rev 2020 02 2;52(1):185-204. Epub 2020 Mar 2.

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.

The neurological disorders affect millions of people worldwide, and are bracketed as the foremost basis of disability-adjusted life years (DALYs). The treatment options are symptomatic and often the movement of drugs is restricted by a specialized network of endothelial cell layers (adjoined by tight cell-to-cell junction proteins; occludin, claudins, and junctional adhesion molecules), pericytes and astroglial foot processes. In recent years, advances in nanomedicine have led to therapies that target central nervous system (CNS) pathobiology via altering signaling mechanisms such as activation of PI3K/Akt pathway in ischemic stroke arrests apoptosis, interruption of α-synuclein aggregation prevents neuronal degeneration in Parkinson's. Often such interactions are limited by insufficient concentrations of drugs reaching neuronal tissues and/or insufficient residence time of drug/s with the receptor. Hence, lipid nanoformulations, SLNs (solid lipid nanoparticles) and NLCs (nanostructured lipid carriers) emerged to overcome these challenges by utilizing physiological transport mechanisms across blood-brain barrier, such as drug-loaded SLN/NLCs adsorb apolipoproteins from the systemic circulation and are taken up by endothelial cells via low-density lipoprotein (LDL)-receptor mediated endocytosis and subsequently unload drugs at target site (neuronal tissue), which imparts selectivity, target ability, and reduction in toxicity. This paper reviews the utilization of SLN/NLCs as carriers for targeted delivery of novel CNS drugs to improve the clinical course of neurological disorders, placing some additional discussion on the metabolism of lipid-based formulations.
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http://dx.doi.org/10.1080/03602532.2020.1726942DOI Listing
February 2020

3'-(4-(Benzyloxy)phenyl)-1'-phenyl-5-(heteroaryl/aryl)-3,4-dihydro-1'H,2H-[3,4'-bipyrazole]-2-carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies.

Arch Pharm (Weinheim) 2020 Apr 31;353(4):e1900262. Epub 2020 Jan 31.

Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

Pyrazoline-linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF-7 (breast cancer), A549 (non-small-cell lung tumor), HCT-116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4',6-diamidino-2-phenylindole (DAPI) staining and phase-contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence-activated cell sorting using Annexin V-FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate-binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non-small-cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.
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http://dx.doi.org/10.1002/ardp.201900262DOI Listing
April 2020

Recent advancement in the discovery and development of COX-2 inhibitors: Insight into biological activities and SAR studies (2008-2019).

Bioorg Chem 2019 08 21;89:103007. Epub 2019 May 21.

Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.

Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among other roles, making it a molecule of high interest to the pharmaceutical community as a target. COX 2 enzyme is induced only during inflammatory processes or cancer and reflects no role in the guarding stomach lining. Thus, selective COX-2 inhibition can significantly reduce the adverse effects including GI tract damage and hepatotoxic effects of traditional NSAIDs like aspirin, ibuprofen, etc. Recent developments on COX-2 inhibitors is primarily focused on improving the selectivity index of the drug towards COX-2 along with enhancing the potency of the drug by modifying the scaffolds of Coxibs currently in the market like Celecoxib, Indomethacin, Oxaprozin, etc. We have reported the progress on new COX-2 inhibitors in the last decade (2008-2019) focussing on five heterocyclic rings- Pyrazole, Indole, Oxazole, Pyridine and Pyrrole. The addition of various moieties to these core rings and their structure-activity relationship along with their molecular modelling data have been explored in the article. This review aims to aid medicinal chemists in the design and discovery of better COX-2 inhibitors constructed on these five heterocyclic pharmacophores.
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http://dx.doi.org/10.1016/j.bioorg.2019.103007DOI Listing
August 2019

Ultra-performance hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma: Application to pharmacokinetic study in rats.

PLoS One 2019 14;14(3):e0213786. Epub 2019 Mar 14.

Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7μm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213786PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417734PMC
December 2019

Design, synthesis, and molecular docking study of benzothiazolotriazine derivatives for anticonvulsant potential.

Arch Pharm (Weinheim) 2018 Dec 27;351(12):e1800154. Epub 2018 Nov 27.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

A series of newer benzothiazolotriazine derivatives (4a-k) was designed, synthesized, and characterized as anticonvulsant agents against the two classically used MES and scPTZ animal models. The synthesized derivatives were tested in vivo in both the animal models, followed by a neurotoxicity study by the rotarod method. Compound 4e, 8-chloro-4-(2-chlorocyclohexa-1,5-dien-1-yl)-2-((4-methoxybenzyl)thio)-10aH-benzo[4,5]thiazolo[3,2a][1,3,5]triazine was found most promising among the series in both the animal models, with no neurotoxicity. From this it may be confirmed that the presence of a methoxy (OCH ) group at the lipophilic aryl ring was showing high anticonvulsant potency. In the molecular modeling study, compound 4e (docking score = -8.70) showed important hydrogen bond interaction with the amino acids LYS 329, SER 137, GLY 136 and π-π interactions with PHE 189 at the active site of GABA-AT. These derivatives can be further explored for the development of newer/novel anticonvulsant agents.
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http://dx.doi.org/10.1002/ardp.201800154DOI Listing
December 2018

1,2,4-Triazole-based benzothiazole/benzoxazole derivatives: Design, synthesis, p38α MAP kinase inhibition, anti-inflammatory activity and molecular docking studies.

Bioorg Chem 2018 12 8;81:630-641. Epub 2018 Sep 8.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. Electronic address:

Novel N-(benzothiazol/oxazol-2-yl)-2-[(5-(phenoxymethyl)-4-aryl-4H-1,2,4-triazol-3-yl)thio] acetamide derivatives (5a-n) were synthesized and investigated for in vitro anti-inflammatory activity and p38α MAP kinase inhibition. Compounds showing good in vitro activities (5a, 5b, 5d, 5e, 5i, 5k and 5l) were studied for their in vivo anti-inflammatory activity using carrageenan induced rat paw edema model. Compound 5b emerged as the most active compound with an edema inhibition of 84.43%. It also showed improved GI safety profile with lower ulcer severity index and lipid peroxidation potential. Also, p38α MAP kinase assay of 5b showed superior inhibitory potency (IC:0.031 ± 0.14 µM) than the standard SB 203580 (IC:0.043 ± 0.14 µM). To predict their binding mode compounds were also docked against p38α MAP kinase enzyme. Compound 5b and SB 203580 showed hinge region interaction with MET 109.
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http://dx.doi.org/10.1016/j.bioorg.2018.09.015DOI Listing
December 2018

Pyrrole: An insight into recent pharmacological advances with structure activity relationship.

Eur J Med Chem 2018 Sep 4;157:527-561. Epub 2018 Aug 4.

Dept. of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Pyrrole is a heterocyclic ring template with multiple pharmacophores that provides a way for the generation of library of enormous lead molecules. Owing to its vast pharmacological profile, pyrrole and its analogues have drawn much attention of the researchers/chemists round the globe to be explored exhaustively for the benefit of mankind. This review focusses on recent advancements; pertaining to pyrrole scaffold, discussing various aspects of structure activity relationship and its bioactivities.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.002DOI Listing
September 2018

Recent advancement of piperidine moiety in treatment of cancer- A review.

Eur J Med Chem 2018 Sep 8;157:480-502. Epub 2018 Aug 8.

Department of Physiology, Hamdard Institute of Medical Sciences & Research, Jamia Hamdard, New Delhi, 110062, India.

Piperidine is an important pharmacophore, a privileged scaffold and an excellent heterocyclic system in the field of drug discovery which provides numerous opportunities in studying/exploring this moiety as an anticancer agent by acting on various receptors of utmost importance. Cancer is an uncontrolled division of cells that results in the formation of tumour which have the potential to migrate to other parts of the body (metastasis) finally becoming a major threat to human population. Since piperidine displayed great potential in this area it is being further probed to get novel entities for the treatment of cancer. This review throws light on recent biological expansions of piperidine along with structure activity relationships to deliver association between various synthesized newer/novel derivatives and receptor sites.
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http://dx.doi.org/10.1016/j.ejmech.2018.08.017DOI Listing
September 2018

Development of Thiazole-5-carboxylate Derivatives as Selective Inhibitors of Monoacylglycerol Lipase as Target in Cancer.

Mini Rev Med Chem 2019 ;19(5):410-423

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi-110062, India.

Introduction: The signalling function of 2-arachidonoylglycerol (2-AG) in endocannabinoid system is delineated by Monoacylglycerol lipase (MAGL). MAGL readdresses the lipid stores in the direction of pro-tumorigenic signalling lipids in cancer cells. Selective as well as potent MAGL inhibitors are limited in number hence their continuous development may lead to a breakthrough invention in the field of MAGL inhibitors. In succession of the above, we have synthesised 2-amino-4- methylthiazole-5-carboxylate derivatives and characterised them by collective use of IR, 1H-NMR, 13C-NMR, Mass spectral data and elemental analysis.

Methodology: Thirteen compounds (3c-g, 4c, 4e, 4f and 6b-f) inhibited MAGL with IC50 value 0.037- 9.60 µM. Two compounds (3g and 4c) were found to be most potent with IC50 values 0.037 and 0.063µM, respectively. Thirty synthesised compounds were sent to NCI for anticancer screening, out of which nine compounds were selected for one dose anticancer assay. Compounds 3g (NSC:788170) and 4c (NSC:788176)were found to be the most potent during one dose anticancer screening and fulfilled the specified threshold for growth inhibition criteria of NCI and were further selected for full panel five dose assay at 10-fold dilutions of five different concentrations.

Conclusion: Compound 3g displayed GI50 value 0.865 μM against EKVX (Non-Small Cell Lung Cancer cell line), and 1.20 µM against MDA-MB-468 (Breast Cancer cell Line), while (4c) showed GI50 value 0.34 and 0.96 µM against HOP-92 and EKVX (Non-Small Cell Lung Cancer cell line) and 1.08 µM against MDA-MB-231/ATCC(Breast Cancer cell Line). In addition, molecular docking studies of the said MAGL inhibitors have also been presented in this article.
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http://dx.doi.org/10.2174/1389557518666180702103542DOI Listing
March 2019

Synthesis, p38α MAP kinase inhibition, anti-inflammatory activity, and molecular docking studies of 1,2,4-triazole-based benzothiazole-2-amines.

Arch Pharm (Weinheim) 2018 Apr 8;351(3-4):e1700304. Epub 2018 Mar 8.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Hamdard University, New Delhi, India.

Recent studies have demonstrated that inhibition of p38α MAP kinase could effectively inhibit pro-inflammatory cytokines including TNF-α and interleukins. Thus, inhibition of this enzyme can prove greatly beneficial in the therapy of chronic inflammatory diseases. A new series of N-[3-(substituted-4H-1,2,4-triazol-4-yl)]-benzo[d]thiazol-2-amines (4a-n) were synthesized and subjected to in vitro evaluation for anti-inflammatory activity (BSA anti-denaturation assay) and p38α MAPK inhibition. Among the compounds selected for in vivo screening of anti-inflammatory activity (4b, 4c, 4f, 4g, 4j, 4m, and 4n), compound 4f was found to be the most active with an in vivo anti-inflammatory efficacy of 85.31% when compared to diclofenac sodium (83.68%). It was also found to have a low ulcerogenic risk and a protective effect on lipid peroxidation. The p38α MAP kinase inhibition of this compound (IC  = 0.036 ± 0.12 μM) was also found to be superior to the standard SB203580 (IC  = 0.043 ± 0.27 μM). Furthermore, the in silico binding mode of the compound on docking against p38α MAP kinase exemplified stronger interactions than those of SB203580.
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http://dx.doi.org/10.1002/ardp.201700304DOI Listing
April 2018

Synthesis, docking, in vitro and in vivo antidiabetic activity of pyrazole-based 2,4-thiazolidinedione derivatives as PPAR-γ modulators.

Arch Pharm (Weinheim) 2018 Apr 5;351(3-4):e1700223. Epub 2018 Feb 5.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, India.

The design, synthesis, structure-activity relationship, and biological activity of 2,4-thiazolidinedione derivatives as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity are reported. Fifteen 2,4-thiazolidinedione derivatives clubbed with pyrazole moiety were docked into the ligand binding domain of PPAR-γ by the Glide XP module of Schrodinger. Eight derivatives (5a, 5b, 5d, 5f, 5i, 5l, 5n, 5o) having Glide XP scores > -8 as compared to the standard drug, rosiglitazone (Glide XP score = -9.165), showed almost similar interaction with the amino acids such as HIS 449, TYR 473, TYR 327, HIS 323, and SER 289 in the molecular docking studies. These eight derivatives were further screened for PPAR-γ transactivation and in vivo blood glucose lowering activity in the streptozotocin-induced diabetic rat model. Compounds 5o, 5n, 5a, 5i, and 5b showed 52.06, 51.30, 48.65, 43.13, and 40.36% PPAR-γ transactivation as compared to the reference drugs rosiglitazone and pioglitazone with 85.30 and 65.22% transactivation, respectively. The data analysis showed significant blood glucose lowering effects (hypoglycemia) of compounds 5o, 5n, and 5a (140.1 ± 4.36, 141.4 ± 6.15, and 150.7 ± 4.15, respectively), along with reference drugs pioglitazone (135.2 ± 4.91) and rosiglitazone (141.1 ± 5.88) as compared to the diabetic control. Furthermore, the most potent compound 5o also elevated the PPAR-γ gene expression by 2.35-fold as compared to rosiglitazone (1.27-fold) and pioglitazone (1.6-fold). It also significantly lowered the AST, ALT, and ALP levels and caused no damage to the liver.
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http://dx.doi.org/10.1002/ardp.201700223DOI Listing
April 2018

Synthesis, anti-inflammatory, p38α MAP kinase inhibitory activities and molecular docking studies of quinoxaline derivatives containing triazole moiety.

Bioorg Chem 2018 02 2;76:343-358. Epub 2017 Dec 2.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Hamdard University, New Delhi 110062, India. Electronic address:

A new series of 3-[2-(5-mercapto-4-phenyl-4H-1,2,4-traiazol-3-yl)ethyl] quinoxalin-2(1H)-one (5a-v) derivatives was synthesized and subjected to in vitro evaluation for anti-inflammatory activity (BSA anti-denaturation assay) and p38α MAPK inhibition. Few selected compounds (5a, 5e, 5f, 5g, 5h, 5l, 5q and 5u) were studied for their in vivo anti-inflammatory activity, ulcerogenicity and lipid peroxidation potential. Compounds 5e and 5f were found to be the most active in the series showing 83.45% and 84.15% anti-inflammatory activity respectively when compared to diclofenac sodium (83.22%). They were also found to have low ulcerogenic potential and lipid peroxidation. The p38α MAP kinase inhibition of the compounds 5e and 5f was also found to be slightly better than the standard SB 203580. The compounds were also docked against p38α MAP kinase enzyme in order to predict their binding mode. Compounds 5e and 5f showed stronger binding with an additional hydrogen bond interaction with ASP-168 which was not observed in SB 203580.
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http://dx.doi.org/10.1016/j.bioorg.2017.12.003DOI Listing
February 2018

Design, synthesis and molecular docking of thiazolidinedione based benzene sulphonamide derivatives containing pyrazole core as potential anti-diabetic agents.

Bioorg Chem 2018 02 16;76:98-112. Epub 2017 Nov 16.

Department of Physiology, Hamdard Institute of Medical Sciences & Research, Jamia Hamdard, New Delhi 110062, India.

We herein report the design, synthesis and molecular docking studies of 2,4-thiazolidinedione derivatives containing benzene sulphonyl group which are docked against the Peroxisome Proliferator Activated Receptor (PPARγ) target. Compound 7p was most effective in lowering the blood glucose level as compared to standard drugs pioglitazone and rosiglitazone. Compound 7p exhibited potent PPAR-γ transactivation of 61.2% with 1.9 folds increase in gene expression. In molecular docking studies 7p showed excellent interactions with amino acids TYR 473, SER 289, HIE 449, TYR 327, ARG 288, MET 329 and LEU 228. Compound 7p did not cause any damage to the liver without any noteworthy weight gain and may be considered as promising candidates for the development of new antidiabetic agents.
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http://dx.doi.org/10.1016/j.bioorg.2017.11.010DOI Listing
February 2018

Design, Synthesis, and Docking Study of Pyrimidine-Triazine Hybrids for GABA Estimation in Animal Epilepsy Models.

Arch Pharm (Weinheim) 2017 Sep 31;350(9). Epub 2017 Jul 31.

Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), New Delhi, India.

A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED ), 285.02 and 293.42 mg/kg (scPTZ ED ), and 389.11 and 412.16 mg/kg (TD ), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs.
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http://dx.doi.org/10.1002/ardp.201700146DOI Listing
September 2017

Synthesis, molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives.

Bioorg Chem 2017 08 6;73:24-36. Epub 2017 May 6.

Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India. Electronic address:

A series of thiazolidinedione based amide derivatives were designed, synthesized and docked against the PPARγ receptor target. 11 compounds from the series with good glide scores were selected for in vivo antidiabetic study based on streptozotocin induced diabetic rat model. It was observed that 4 compounds (6c, 6e, 6m &6n) showed significantly good antidiabetic activity in comparison to rosiglitazone and pioglitazone as reference drugs. Compound 6c appeared as the most potent derivative in lowering blood glucose level and showed excellent interaction with SER 342, ILE 281, pi-pi interaction with ARG 288 and halogen bond interaction with LYS 367. Further, PPARγ transactivation and gene expression studies of compound 6c were carried out to investigate the possible mechanism of action through PPARγ modulation. Compound 6c exhibited 53.65% transactivation and elevated PPARγ gene expression by 2.1 folds. The biochemical parameters (AST, ALT and ALP levels) were found within the range with no noteworthy damage to liver.
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http://dx.doi.org/10.1016/j.bioorg.2017.05.007DOI Listing
August 2017
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