Publications by authors named "Zabeer Ahmed"

26 Publications

  • Page 1 of 1

Novel alantolactone derivative AL-04 exhibits potential anti-inflammatory activity via modulation of iNOS, COX-2 and NF-κB.

Cytokine 2022 Jul 31;158:155978. Epub 2022 Jul 31.

Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir 180001, India. Electronic address:

Natural compounds and their synthesized analogues continue to be valuable sources in the discovery and development of novel anti-inflammatory agents. AL-04 is a thiol analogue derived from a natural sesquiterpene alantolactone, that demonstrated potential anti-inflammatory activity in vitro in comparison to its parent compound. However, the anti-inflammatory mechanism of action of AL-04 has not been elucidated. In this context, we investigated the signaling pathway that primarily mediate the anti-inflammatory activity of AL-04 and its effect on principal inflammatory mediators including iNOS, COX-2 and ROS. Furthermore, the anti-inflammatory activity was investigated in vivo in carrageenan induced paw oedema model in addition to the exploration of anti-nociceptive activity and acute toxicity. The results suggested that treatment with AL-04 significantly decreased the LPS-induced upregulation of pro-inflammatory cytokines and mediators in addition to the downregulated transcription of TNF-α and IL-6 in RAW 264.7 cell line. Furthermore, mRNA and the protein expression of COX-2 and iNOS were also significantly attenuated with AL-04 at a concentration of 10 µM. Western blot studies further suggested that AL-04 downregulated LPS-stimulated NF-κB p65 expression. In addition to this the anti-inflammatory activity of AL-04 was demonstrated in carrageenan induced paw oedema model with significant inhibition of oedema in a dose-dependent manner. The anti-inflammatory activity of AL-04 was further demonstrated in balb/c mice by inhibition of leukocyte migration and vascular permeability. Besides, AL-04 also inhibited thermally and chemically induced pain in tail-flick and acetic acid induced writing assays respectively in balb/c mice suggesting the analgesic potential of the compound. Acute toxicity studies further suggested the appreciable safety of AL-04 at high dose of 2000 mg/kg with no indications of toxicity or changes in biochemical and haematological parameters. Overall, the study insinuates the anti-inflammatory potential of AL-04 and paves way for further exploration of the compound as a safer therapeutic anti-inflammatory agent.
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http://dx.doi.org/10.1016/j.cyto.2022.155978DOI Listing
July 2022

Corrigendum to "Evaluation of the immunomodulatory and anti-inflammatory activity of Bakuchiol using RAW 264.7 macrophage cell lines and in animal models stimulated by lipopolysaccharide (LPS)" [Int. Immunopharmacol. 91 (2021) 107264].

Int Immunopharmacol 2022 Jun 28:109003. Epub 2022 Jun 28.

Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Mutagenicity Laboratory, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Laboratory Animal Facility, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address:

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http://dx.doi.org/10.1016/j.intimp.2022.109003DOI Listing
June 2022

Phytochemicals targeting JAK/STAT pathway in the treatment of rheumatoid arthritis: Is there a future?

Biochem Pharmacol 2022 03 19;197:114929. Epub 2022 Jan 19.

Pharmacology Division, CSIR- Indian Institute of Integrative Medicine, Canal Road, Jammu, J&K 180001, India. Electronic address:

Rheumatoid arthritis (RA) is a chronic autoimmune disorder and the treatment involves the use of traditional and biological disease modifying anti-rheumatic drugs (DMARDs). Recent studies have shown JAK/STAT signaling pathway as potential target for the treatment of RA. Novel JAK/STAT inhibitors viz tofacitinib and baricitinib have been recently approved by FDA for RA treatment and have attained substantial importance. However, the discernible risks of thromboembolism, gastrointestinal (GIT) perforations, hepatotoxicity and serious infections including tuberculosis, herpes zoster associated with their administration cannot be overlooked. Furthermore, these are highly expensive which limits their application for a broader use. These limitations provide the basis of exploring novel JAK/STAT inhibitors of natural origin with increased tolerability, safety and cost-effectiveness. In this review we confer an account of various natural compounds/phytochemicals that have proved to be beneficial in attenuating inflammation in RA via modulation of JAK/STAT signaling pathway. Some of these natural compounds including resveratrol have clearly indicated biochemical and clinically significant therapeutic effects in ameliorating RA both in vivo and in clinical settings. We further discuss the physicochemical challenges of poor solubility and absorption coupled with the use of natural JAK/STAT inhibitors. We thereafter discuss and summarize various drug delivery systems (DDS) to confront the physicochemical limitations of natural JAK/STAT inhibitors with the aim to enhance the therapeutic efficacy. Overall the review unveils the potential of natural JAK/STAT inhibitors as a cost-effective approach in ameliorating RA without incorporating the risks of adverse repercussions, thus setting the stage for clinical exploration of these compounds that may possibly complement the present RA therapy.
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http://dx.doi.org/10.1016/j.bcp.2022.114929DOI Listing
March 2022

Dereplication Based Strategy for Rapid Identification and Isolation of a Novel Anti-inflammatory Flavonoid by LCMS/MS from .

ACS Omega 2021 Nov 2;6(45):30241-30259. Epub 2021 Nov 2.

Natural Product Chemistry Division, Analytical Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.

is a folkloric medicinal plant, well known for its tremendous medicinal properties such as curing epilepsy, ulcers, and urinary problems. The aim of the present study was to apply the dereplication strategy on the ethanol extract of with potent anti-inflammatory activity for the rapid identification and isolation of novel bioactive molecules to aid the drug discovery process. An integrated approach using liquid chromatography-mass spectrometry (LCMS) followed by preparative high-performance liquid chromatography (HPLC) was used for the isolation of potent molecules from the anti-inflammatory extract of Purity of the compounds (>98.5%) was established by HPLC, and identification was carried out by NMR and ESI-MS. 5,6,7-Trihydroxyflavone-3--glucuronide methyl ester (compound III) isolated from was extensively studied for anti-inflammatory potential in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the mice model. Compound III significantly repressed various proinflammatory mediators and upregulated the release of anti-inflammatory cytokine IL-10. Compound III reduced inflammation when studied for parameters such as the phagocytic index, carrageenan-induced paw edema in mice, and effect on organ weight. It reduced inflammation in a dose-dependent manner both and . Further molecular insights into the study revealed that compound III blocks the phosphorylation of I kappa b kinase α/β (IKKα/β), IκBα, and nuclear factor kB p65 (NF-κBp65) which is a key controller of inflammation, thereby showing anti-inflammatory potential. Hence, this study permits further investigation to develop compound III as an anti-inflammatory drug.
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http://dx.doi.org/10.1021/acsomega.1c01837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600527PMC
November 2021

Site selective synthesis and anti-inflammatory evaluation of Spiro-isoxazoline stitched adducts of arteannuin B.

Bioorg Chem 2021 12 9;117:105408. Epub 2021 Oct 9.

Natural Product and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India; CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi 110007, India. Electronic address:

A library of new spiroisoxazoline analogues of arteannuin B was synthesized through 1, 3-dipolar cycloaddition in stereoselective fashion and consequently screened for anti-inflammatory activity in RAW 264.7 macrophage cells. Three potent analogues (8i, 8 m, and 8n) were found to attenuate the LPS induced release of cytokines IL-6 and TNF-α more potently than the parent molecule. Also, the inhibition of LPS induced nitric oxide production in these cells show moderate to high efficacy. None of the three potent molecules have altered the viability of RAW 264.7 cells following 48 h incubation suggesting that the inhibition of cytokines and nitric oxide production exhibited in the cells was not due to toxicity. In addition, these compounds exhibit an IC range of 0.17 µM-1.57 µM and 0.09 µM-0.35 µM for the inhibition of IL-6 release and nitric oxide production respectively. The results disclose potent inhibition of pro-inflammatory mediators which are encouraging and warrant further investigations to develop new therapeutic agents for inflammatory diseases.
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http://dx.doi.org/10.1016/j.bioorg.2021.105408DOI Listing
December 2021

Phytochemical add-on therapy to DMARDs therapy in rheumatoid arthritis: In vitro and in vivo bases, clinical evidence and future trends.

Pharmacol Res 2021 07 18;169:105618. Epub 2021 Apr 18.

Inflammation Pharmacology Division, CSIR, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J&K, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India. Electronic address:

The use of biologically active compounds derived from plants i.e. phytochemicals, have been known for ages for their pharmacological activities in the treatment of autoimmune disorders like rheumatoid arthritis (RA). Besides enormous scientific evidence, the therapeutic potential of phytochemicals is often undervalued. The treatment in RA involves the use of synthetic and biological disease modifying anti-rheumatic drugs (DMARDs). However, the long-term treatment in RA is associated with the risk of gastrointestinal, liver, pulmonary and renal toxicities and serious infections including latent tuberculosis, pneumococcus influenza, herpes zoster and hepatitis. These adverse effects sometimes lead to discontinuation of the therapy. A relatively new vision based on the combination of DMARDs with phytochemicals exhibiting anti-inflammatory, anti-arthritic, anti-oxidant, hepatoprotective and nephroprotective properties for the treatment of RA has achieved substantial importance in the last decade. From this perspective, the present review focuses on the combination of DMARDs (primarily MTX) with phytochemicals that have shown synergistic therapeutic effects while decreasing the toxic repercussions of current RA therapy. The review covers recent evidences of such combination studies that have shown promising results both in experimental arthritic models and clinical arthritis. Few of the combinations including resveratrol, sinomenine, coenzyme Q10 exhibited considerable interest because of their efficacy as an adjuvant to the MTX/standard DMARDs therapy in clinical trials. Besides giving an overview of such combination studies the review also critically discusses the limitations with the use of phytochemicals (e.g. solubility, permeability and bioavailability) compromising their clinical application. Additionally, it stresses upon the need of novel delivery systems and pharmaceutical technologies to increase the therapeutic efficacy of the combination therapy. Overall, the review unveils the potential of phytochemicals in combination with DMARDs with increased tolerability and superior efficacy in further refining the future of the RA therapy.
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http://dx.doi.org/10.1016/j.phrs.2021.105618DOI Listing
July 2021

Evaluation of the immunomodulatory and anti-inflammatory activity of Bakuchiol using RAW 264.7 macrophage cell lines and in animal models stimulated by lipopolysaccharide (LPS).

Int Immunopharmacol 2021 Feb 16;91:107264. Epub 2020 Dec 16.

Academy of Science and Innovative Research (AcSIR), New Delhi, India; Mutagenicity Laboratory, CSIR- Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Laboratory Animal Facility, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address:

Bakuchiol (BAK) has been reported to have a diverse pharmacological property as an antibiotic, anti-cancer, anti-hypolipidemic, anti-inflammatory and anti-convulsant agent. This study aimed to elucidate the immunomodulation and anti-inflammatory mechanism of bakuchiol using lipopolysaccharide stimulated RAW 264.7 macrophages and various animal models. The present study has shown that BAK significantly suppressed the pro-inflammatory cytokine expression in a dose-dependent manner and its oral administration significantly decreased delayed hypersensitivity responses as compared to control group. The assessment of immunomodulatory activity was carried out by the testing Hemagglutinating antibody (HA) titer, delayed type hypersensitivity (DTH) responses and phagocytic index by carbon clearance test. On the other hand, it showed significant decrease in circulating antibody titer and carbon clearance assay in a concentration-dependent manner. BAK has significantly potentiated the cellular immunity as well as humoral immunity by facilitating the footpad thickness responses in sheep RBCs in sensitized mice by significantly decreasing circulating antibody titer. Molecular studies revealed that BAK inhibited the activation of upstream mediator nuclear factor-κB by suppressing the phosphorylation of IκBα and p65. The responses were statistically significant as compared with the control (*p < 0.05, **p < 0.01).
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http://dx.doi.org/10.1016/j.intimp.2020.107264DOI Listing
February 2021

Origanum vulgare L.: In vitro Assessment of Cytotoxicity, Molecular Docking Studies, Antioxidant and Anti-inflammatory Activity in LPS Stimulated RAW 264.7 Cells.

Med Chem 2021 ;17(9):983-993

Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar 190006, Kashmir, India.

Background: Inflammation involves a dynamic network that is highly regulated by signals that initiate the inflammation process as well as signals that downregulate it. However, an imbalance between the two leads to tissue damage. Throughout the world, inflammatory disease becomes common in the aging society. The drugs which are used clinically have serious side effects. Natural products or compounds derived from natural products show diversity in structure and play an important role in drug discovery and development.

Objective: Oreganum Vulgare is used in traditional medicine for various ailments including respiratory and rheumatic disorders, severe cold, suppression of tumors. The current study aims to evaluate the anti-inflammatory potential by evaluating various in vitro parameters.

Methods: Inflammation-induced in macrophages via LPS is the most accepted model for evaluating the antiinflammatory activity of various plant extracts and lead compounds.

Results: The extracts (OVEE, OVEAF) as well as the isolated compound(OVRA)of Oreganum Vulgare inhibit the pro-inflammatory cytokines (IL-6 and TNF-α) and NO without affecting cell viability.

Conclusion: Our study established that the leaf extracts of Oreganum vulgare L. exhibit anti-inflammatory activity and thus confirm its importance in traditional medicine.
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http://dx.doi.org/10.2174/1573406416666200904110828DOI Listing
December 2021

Role of environmental pollutants in Alzheimer's disease: a review.

Environ Sci Pollut Res Int 2020 Dec 27;27(36):44724-44742. Epub 2020 Jul 27.

Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal, Srinagar, Kashmir, 190006, India.

Neurodegenerative disorders are commonly erratic influenced by various factors including lifestyle, environmental, and genetic factors. In recent observations, it has been hypothesized that exposure to various environmental factors enhances the risk of Alzheimer's disease (AD). The exact etiology of Alzheimer's disease is still unclear; however, the contribution of environmental factors in the pathology of AD is widely acknowledged. Based on the available literature, the review aims to culminate in the prospective correlation between the various environmental factors and AD. The prolonged exposure to the various well-known environmental factors including heavy metals, air pollutants (particulate matter), pesticides, nanoparticles containing metals, industrial chemicals results in accelerating the progression of AD. Common mechanisms have been documented in the field of environmental contaminants for enhancing amyloid-β (Aβ) peptide along with tau phosphorylation, resulting in the initiation of senile plaques and neurofibrillary tangles, which results in the death of neurons. This review offers a compilation of available data to support the long-suspected correlation between environmental risk factors and AD pathology. Graphical abstract .
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http://dx.doi.org/10.1007/s11356-020-09964-xDOI Listing
December 2020

Acteoside ameliorates inflammatory responses through NFkB pathway in alcohol induced hepatic damage.

Int Immunopharmacol 2019 Apr 28;69:109-117. Epub 2019 Jan 28.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, India. Electronic address:

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http://dx.doi.org/10.1016/j.intimp.2019.01.020DOI Listing
April 2019

Murrayanine Attenuates Lipopolysaccharide-induced Inflammation and Protects Mice from Sepsis-associated Organ Failure.

Basic Clin Pharmacol Toxicol 2019 Apr 22;124(4):351-359. Epub 2019 Jan 22.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicines, Jammu Tawi, Jammu and Kashmir, India.

Murrayanine (MK) is the main compound isolated from Murraya koenigii, an aromatic plant belonging to the Rutaceae family, also known as curry leaf tree. Murrayanine was reported to possess potential antioxidant, antimycobacterial and antifungal effects. However, its effect in sepsis remains unclear. This study was designed to investigate the anti-inflammatory effect of MK using both in vitro and in vivo assay. Results of this study indicated that MK decreased NO, TNF-α and IL-6 production in both lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and murine peritoneal macrophages. Moreover, iNOS and COX-2 protein expression as well as their downstream product, PGE2, was also decreased effectively in RAW 264.7 cells. Furthermore, MK decreased the phosphorylation of IKB and repressed NF-kB activity in LPS-activated RAW 264.7 cells. Additionally, we evaluated MK efficacy in vivo using LPS-induced sepsis, a systemic inflammation model in mice. Administration of MK inhibits pro-inflammatory cytokines (TNF-α and IL-6) secretion; decreases AST, ALT, BUN and CRE level in mouse sera; mitigates lung, liver and kidney injuries; and also increases LPS-challenged mice survival rate. Collectively, our results suggest that MK exerts potential as a new anti-inflammatory and immunosuppressive drug in sepsis treatment.
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http://dx.doi.org/10.1111/bcpt.13032DOI Listing
April 2019

Correction: Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities.

Org Biomol Chem 2018 03;16(11):1994

Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, J&K 180001, India.

Correction for 'Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities' by Yedukondalu Nalli et al., Org. Biomol. Chem., 2016, 14, 3322-3332.
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http://dx.doi.org/10.1039/c8ob90030bDOI Listing
March 2018

Kaempferol-3-o-β-d-glucuronate exhibit potential anti-inflammatory effect in LPS stimulated RAW 264.7 cells and mice model.

Int Immunopharmacol 2018 Apr 22;57:62-71. Epub 2018 Feb 22.

Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicines, Jammu Tawi, Jammu and Kashmir, India. Electronic address:

Kaempferol-3-O-β-d-glucuronide (K3G) having various pharmacological effects was explored for its anti-inflammatory effect in LPS induced RAW 264.7 cells and mice model. K3G significantly inhibited various pro-inflammatory mediators like IL-1β, NO, PGE2, and LTB4. It upregulated the secretion of anti-inflammatory cytokine IL-10. K3G is found to reduce inflammation when studied for parameters like phagocytic index, carrageenan induced paw edema in mice and organ weight. It reduced inflammation in a dose dependent manner both in-vitro and in-vivo. Further molecular insights into the study reveal that K3G blocks the phosphorylation of NF-kB which is key regulator of inflammation, thereby exhibiting anti-inflammatory potential. Hence, this study permits further investigation to develop K3G as anti-inflammatory drug.
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http://dx.doi.org/10.1016/j.intimp.2018.01.041DOI Listing
April 2018

The amino analogue of β-boswellic acid efficiently attenuates the release of pro-inflammatory mediators than its parent compound through the suppression of NF-κB/IκBα signalling axis.

Cytokine 2018 07 8;107:93-104. Epub 2017 Dec 8.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicines, India. Electronic address:

Natural product derivatives have proven to be cutting edge window for drug discovery and development. BA-25 (3-α-o-acetoxy-4β-amino-11-oxo-24-norurs-12-ene) an amino analogue of β-boswellic acid exhibited inhibition of TNF-α and IL-6 in THP-1 cells as demonstrated previously, however, the effect on principal inflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and the pathways that mediate this function remains unknown. This study was designed to examine the comparative anti-inflammatory activity of BA-25 with its parent compound, β boswellic acid both in vitro and in vivo. The effect of BA and BA-25 on suppression of NO, PGE LTB, COX-2 in LPS-stimulated RAW 264.7 cells was determined by ELISA, RT-PCR and ROS by flow cytometry. Phosphorylation of NF-kBp65, IKB degradation was determined by western blotting and also the nuclear localization of NF-kBp65 was assessed by immunofluorescence. Furthermore, this study was extended on Carrageenan induced paw oedema modelled BALB/c mice. A novel derivative BA-25, reported first time notably decreased the LPS (1 μg/mL) induced upregulation in the transcription of TNF-α, IL-6, iNOS and COX-2. Also the protein expression of iNOS and COX-2 as well as their downstream products NO and PGE2 respectively, were also decreased efficiently at a concentration of 10 μM than BA. Moreover, LPS upregulated NF-kB p65 expression and IκB degradation was significantly decreased after BA-25 treatment. In addition, the treatment of BA-25 also restored the paw oedema and decreased the magnitude of histopathological alterations. Our data together suggested that BA-25 might be regarded as prospective therapeutic anti-inflammatory alternative and demands further investigation in pharmacological studies.
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http://dx.doi.org/10.1016/j.cyto.2017.12.004DOI Listing
July 2018

Biopharmaceutic parameters, pharmacokinetics, transport and CYP-mediated drug interactions of IIIM-017: A novel nitroimidazooxazole analogue with anti-tuberculosis activity.

Eur J Pharm Sci 2017 Aug 26;106:71-78. Epub 2017 May 26.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine (IIIM), Canal Road, Jammu 180001, J&K, India. Electronic address:

Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated. The results demonstrated that IIIM-017 exhibited good physicochemical properties, comparable to PA-824 and OPC-67683. Caco-2 transport studies revealed that the compound was highly permeable with P of 8.85×10 (A-B) and 27.69×10 (B-A) cm/s. Caco-2 cells were also used to study P-gp mediated transport and inhibition. IIM-017 exhibited very low intrinsic clearance and no substantial hepatotoxicity in vitro. The compound did not have any inhibitory effect on human CYPs 1A2, 2C9, 2D6, 3A4 and 2C19 up to concentration of 30μM. In vivo pharmacokinetics was performed on balb/c mice at 5mg/kg (p.o) and 2.5mg/kg (i.v.) and plasma drug concentrations were determined by LC-MS/MS. The compound showed satisfactory PK parameters in mice. The results insinuate that IIIM-017 should undergo further development as a potential treatment for tuberculosis.
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http://dx.doi.org/10.1016/j.ejps.2017.05.053DOI Listing
August 2017

Anti-inflammatory potential of hentriacontane in LPS stimulated RAW 264.7 cells and mice model.

Biomed Pharmacother 2017 Aug 23;92:175-186. Epub 2017 May 23.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicines, India. Electronic address:

Hentriacontane, has various pharmacological effects including anti-inflammatory, antitumor and antimicrobial activities. Its anti-inflammatory potential has been demonstrated in peritoneal macrophages. However detailed studies on other models elucidating the mechanistic description of the mode of action has not been done. Hence, the aim of the present study is to evaluate the anti-inflammatory potential of hentriacontane both in-vivo (Balb/c mice) and in-vitro (RAW 264.7 cells). Cytokine inhibition of both pro-inflammatory (TNF-α, IL-6, MCP-1 and IL-1β) and anti-inflammatory (IL-10) cytokines was studied in RAW 264.7 cells and Balb/c mice. Suppressive potential of hentriacontane on NO, PGE, LTB4 and on LPS induced translocation of NF-κB in RAW 264.7 cells was studied. Further investigations on the effect of hentriacontane on phagocytic index, carrageenan induced paw oedema in mice and on organ weight were done. It was found that hentriacontane significantly reduced all the parameters of inflammation in the experiments under study at all the concentrations, 10μM, 5μM and 1μM (in-vitro) and 5mg/kg, 2mg/kg and 1mg/kg (in-vivo). The highest concentration used in the two models presented the most significant results. The results indicate that hentriacontane is a potent suppressor of inflammatory cytokines and other mediators. Moreover it also has regulatory effect on NF-κB. Hence, hentriacontane is a potential candidate for investigations to develop anti-inflammatory drug.
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http://dx.doi.org/10.1016/j.biopha.2017.05.063DOI Listing
August 2017

Synthesis of α-santonin derivatives for diminutive effect on T and B-cell proliferation and their structure activity relationships.

Eur J Med Chem 2017 Feb 9;127:1047-1058. Epub 2016 Nov 9.

Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address:

A new library of 20 compounds from α-santonin was synthesized and tested against Con-A induced T-cell proliferation and LPS-induced B-cell proliferation via MTT assay. The study resulted in the identification of potent immunosuppressant molecules, which were further screened along with α-santonin for Tumor Necrosis Factor Alpha (TNF-α) inhibitory activity. One of the molecules (7) at 10 μM showed equipotency to that of dexamethasone (1 μM conc.) used as a standard. Structure activity relationships of the synthesized compounds along with our earlier reported α-santonin derivatives have been studied. Inferences from the modifications carried out at all the three sites of α-santonin have been elaborated. Computational study of the active compounds shows TNF-α protein as its preferable target rather than Inosine Monophosphate Dehydrogenase (IMPDH).
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http://dx.doi.org/10.1016/j.ejmech.2016.11.018DOI Listing
February 2017

Preclinical comprehensive physicochemical and pharmacokinetic profiling of novel nitroimidazole derivative IIIM-019 - A potential oral treatment for tuberculosis.

Pulm Pharmacol Ther 2016 10 25;40:44-51. Epub 2016 Jul 25.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, J&K, India. Electronic address:

New compounds against tuberculosis are urgently needed to combat the crisis of drug resistance in tuberculosis (TB). We have identified a nitrodihydroimidazooxazole analog, IIIM-019 as a new anti-tubercular agent with a MIC of 0.23 μM against H37Rv. Physicochemical properties, in-vitro pharmacokinetics and in-vivo multiple-doses pharmacokinetics were studied for the compound. In silico physicochemical parameters and Lipinski's violations were determined for drug like properties. Lipophilicity was determined experimentally as Octanol-PBS partition coefficient (log P). Passive and active permeability of the compound was determined by PAMPA and Caco-2 cell permeability analysis, respectively. Plasma protein binding was determined by Rapid equilibrium dialysis. Metabolism by liver microsomes revealed the t1/2 and intrinsic clearance of the compound. Hepatotoxicity of IIIM-019 was determined alone and in combination to first line anti-tubercular drugs. The compound was also estimated for nuclear DNA damage. Single doses of IIIM-019 (2.5, 10, 25 and 100 mg/kg) were administered orally to Balb/c mice and the blood samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). IIIM-019 exhibited very good lipophilicity (log P) of 2.47 which makes it optimal for oral administration. The compound showed low solubility and permeability and high plasma protein binding. However, it was highly stable in rat liver microsomes with t1/2 > 2 h and very low intrinsic clearance. It was found to be non-hepatotoxic and did not induce any significant DNA damage at high concentrations even up to 100 μM. IIIM-019 showed satisfactory in-vivo pharmacokinetic properties. By increasing the dose from 2.5 mg/kg to 10 mg/kg, AUC0-t increased from 14935 ng h/ml to 81,478 ng h/ml. However the exposure of IIIM-019 in plasma suggested that the levels reached saturation at higher concentrations. The compound showed a good oral bioavailability of 58.7%. The results insinuate that IIIM-019 should undergo further development as a potential treatment for tuberculosis.
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http://dx.doi.org/10.1016/j.pupt.2016.06.009DOI Listing
October 2016

Four new carbazole alkaloids from Murraya koenigii that display anti-inflammatory and anti-microbial activities.

Org Biomol Chem 2016 03;14(12):3322-32

Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, J&K 180001, India. and Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, J&K 180001, India.

In our present study, four new, designated as murrayakonine A-D (), along with 18 known carbazole alkaloids were isolated from CHCl3 : MeOH (1 : 1) crude extracts of the stems and leaves of Murraya koenigii (Linn.) Spreng. The structures of the all isolated compounds were characterized by analysis of HR-ESI-MS and NMR (1D and 2D spectroscopy) results, and comparison of their data with the literature data. For the first time, all the isolates were evaluated for their anti-inflammatory activities, using both in vitro and in vivo experiments, against the key inflammatory mediators TNF-α and IL-6. The new compound murrayakonine A (), O-methylmurrayamine A () and murrayanine () were proven to be the most active, efficiently inhibiting TNF-α and IL-6 release in a dose-dependent manner and showing decreased LPS induced TNF-α and IL-6 production in human PBMCs [corrected]. Furthermore, all the isolates were screened for their antimicrobial potential, and the compounds girinimbine () (IC50 3.4 μM) and 1-hydroxy-7-methoxy-8-(3-methylbut-2-en-1-yl)-9H-carbazole-3-carbaldehyde () (IC50 10.9 μM) displayed potent inhibitory effects against Bacillus cereus. Furthermore, compounds murrayamine J () (IC50 11.7 μM) and koenimbine () (IC50 17.0 μM) were active against Staphylococcus aureus. However, none of the compounds were found to be active against Escherichia coli or Candida albicans.
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http://dx.doi.org/10.1039/c6ob00267fDOI Listing
March 2016

Biological Evaluation of Pupalia lappacea for Antidiabetic, Antiadipogenic, and Hypolipidemic Activity Both In Vitro and In Vivo.

Scientifica (Cairo) 2016 28;2016:1062430. Epub 2016 Jan 28.

Department of Pharmacology, Indian Institute of Integrative Medicine, Jammu, Jammu and Kashmir 180001, India.

Objective. The present study assesses the effect of Pupalia lappacea (L.) Juss. (Amaranthaceae) (PL) leaves ethanolic extract on adipocytes, blood glucose level, and lipid level in streptozotocin (STZ) induced diabetic rats. Materials and Methods. Male Albino rats were rendered diabetic by a single moderately sized dose of STZ (45 mg/kg, intraperitoneally) at once before starting the treatment. Animals were divided into five groups: normoglycemic control, diabetic control, reference group (glibenclamide, 5.0 mg/kg), AS001 (250 mg/kg extract), and AS002 (500 mg/kg extract) each containing six animals for in vivo study. Antidiabetic and hypolipidemic activity of extract were determined by in vivo method on STZ induced diabetic rats. Antiadipogenic activity was determined by in vitro method on 3T3-L1 cell line in comparison to simvastatin as reference drug. Result. The extract showed significant fall in fasting serum glucose (FSG), that is, 234.68 and 211.61 mg/dL, in STZ induced diabetic animals for dose groups AS001 and AS002, respectively. The PL extract also exhibited noteworthy antiadipogenic activity on 3T3-L1 cell line. The value of inhibitory concentration (IC50) of PL extract to reduce adipocyte cells was found to be 662.14 μg/mL. Conclusion. The PL extract exhibited significant antiadipogenic, antidiabetic, and hypolipidemic activities.
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http://dx.doi.org/10.1155/2016/1062430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749799PMC
March 2016

Development and validation of a highly sensitive LC-MS/MS-ESI method for quantification of IIIM-019-A novel nitroimidazole derivative with promising action against Tuberculosis: Application to drug development.

J Pharm Biomed Anal 2016 May 22;124:26-33. Epub 2016 Feb 22.

Inflammation Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, J&K, India. Electronic address:

The study aims to illustrate an analytical validation of a rapid and sensitive liquid chromatography (LC) coupled to tandem mass spectrometry (MS-MS) and electrospray ionization (ESI) method for quantification of IIIM-019 (a novel nitroimidazole derivative with potential activity against Tuberculosis) in mice plasma. The extraction of the analyte and the internal standard (Tolbutamide) from the plasma samples involves protein precipitation using acetonitrile. The chromatographic separation was accomplished using a gradient mode and the mobile phase comprised of acetonitrile and 0.1% formic acid in water. The flow rate used was 0.7 ml/min on a C18e high performance Chromolith column. IIIM-019 and Tolbutamide (IS) were analyzed by combined reversed-phase LC/MS-MS with positive ion electrospray ionization. The MS-MS ion transitions used were 533>170.1, 533>198 for IIIM-019 and 271>74, 271>155 for internal standard (IS) respectively. The method was linear over a concentration range of 0.5-1000 ng/ml and the lower limit of quantification was 0.50 ng/ml. The entire study was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification (LLOQ), recovery, and matrix effect in accordance with the FDA guidelines of method validation. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. The intra and inter-day precisions were in the range of 0.51-11.18% and 0.51-7.55%. The pharmacokinetics was performed on male Balb/c mice by oral (2.5mg/kg), intraperitoneal (2.5mg/kg) and intravenous (1mg/kg) routes. The oral bioavailability of IIIM-019 was 51.6%. The method was also applied successfully in determining microsomal stability wherein the compound was found to be very slightly metabolized by rat liver microsomes.
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http://dx.doi.org/10.1016/j.jpba.2016.02.027DOI Listing
May 2016

Analogues of boswellic acids as inhibitors of pro-inflammatory cytokines TNF-α and IL-6.

Bioorg Med Chem Lett 2016 Jan 12;26(2):695-698. Epub 2015 Nov 12.

Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, J&K 180001, India; Natural Product Microbes, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, J&K 180001, India. Electronic address:

A library of boswellic acid analogues were synthesized and tested for their anti-inflammatory potential on key inflammatory mediators, TNF-α and IL-6. The study led to the identification of lead compounds showing significant inhibition of the cytokines, TNF-α and IL-6 both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2015.11.035DOI Listing
January 2016

Par-4 dependent modulation of cellular β-catenin by medicinal plant natural product derivative 3-azido Withaferin A.

Mol Carcinog 2016 May 12;55(5):864-81. Epub 2015 May 12.

Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, Jammu and Kashmir, India.

Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating β-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear β-catenin and augmented its cytoplasmic pool as evidenced by reducing β-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3β (by Akt) to promote β-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear β-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear β-catenin level suggesting Par-4 mediated β-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total β-catenin and decreased expression of phospho-β-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and β-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated β-catenin signaling by 3-AWA induced Par-4 protein.
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http://dx.doi.org/10.1002/mc.22328DOI Listing
May 2016

The anti-angiogenic and cytotoxic effects of the boswellic acid analog BA145 are potentiated by autophagy inhibitors.

Mol Cancer 2015 Jan 21;14. Epub 2015 Jan 21.

Department of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, 180001, India.

Background: While angiogenesis inhibitors represent a viable cancer therapy, there is preclinical and clinical data to suggest that many tumors develop resistance to such treatments. Moreover, previous studies have revealed a complex association between autophagy and angiogenesis, and their collective influence on tumorigenesis. Autophagy has been implicated in cytoprotection and tumor promotion, and as such may represent an alternative way of targeting apoptosis-resistant cancer cells. This study explored the anti-cancer agent and boswellic acid analog BA145 as an inducer of autophagy and angiogenesis-mediated cytoprotection of tumor cells.

Methods: Flow cytometry, western blotting, and confocal microscopy were used to investigate the role of BA145 mediated autophagy. ELISA, microvessel sprouting, capillary structure formation, aortic ring and wound healing assays were performed to determine the relationship between BA145 triggered autophagy and angiogenesis. Flow cytometery, western blotting, and microscopy were employed to examine the mechanism of BA145 induced cell death and apoptosis. Live imaging and tumor volume analysis were carried out to evaluate the effect of BA145 triggered autophagy on mouse tumor xenografts.

Results: BA145 induced autophagy in PC-3 cancer cells and HUVECs significantly impeded its negative regulation on cell proliferation, migration, invasion and tube formation. These effects of BA145 induced autophagy were observed under both normoxic and hypoxic conditions. However, inhibition of autophagy using either pharmacological inhibitors or RNA interference enhanced the BA145 mediated death of these cells. Similar observations were noticed with sunitinib, the anti-angiogenic properties of which were significantly enhanced during combination treatments with autophagy inhibitors. In mouse tumor xenografts, co-treatment with chloroquinone and BA145 led to a considerable reduction in tumor burden and angiogenesis compared to BA145 alone.

Conclusion: These studies reveal the essential role of BA145 triggered autophagy in the regulation of angiogenesis and cytoprotection. It also suggests that the combination of the autophagy inhibitors with chemotherapy or anti-angiogenic agents may be an effective therapeutic approach against cancer.
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http://dx.doi.org/10.1186/1476-4598-14-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509694PMC
January 2015

In-vitro and in-vivo antiadipogenic, hypolipidemic and antidiabetic activity of Diospyros melanoxylon (Roxb).

J Ethnopharmacol 2014 Sep 8;155(2):1171-6. Epub 2014 Jul 8.

University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India. Electronic address:

Ethnopharmacological Relevance: The plant Diospyros melanoxylon (Roxb) belongs to the family Ebenaceae that is native to India and Sri-lanka. This is a medium-sized tree, reaching a height of 15 m and is well known for its beedi making leaves throughout the world. The purpose of the present study is to assess the effect of Diospyros melanoxylon leaves petroleum ether extract on blood glucose level, lipid level, insulin level, body weight, water and food intake in Streptozotocin (STZ) induced diabetic rats.

Materials And Methods: Two different doses of extract AK001 (250 mg/kg) and AK002 (500 mg/kg) of Diospyros melanoxylon leaves were taken to evaluate different activities. The animals were divided into five groups namely normal control, diabetic control, reference group, AK001 and AK002 each containing six animals for in-vivo study. In-vitro study for antiadipogen activity was performed on 3T3-L1 cell line.

Results: The extract showed dose dependent fall in Fasting Glucose Level (FSG) in experimental diabetic animals with significant reduction in food and water intake and increase in body weight. The extract exhibited hypocholesterolemic and hypotriglyceridemic effects while increased level of HDL in diabetes induced rats. In-vitro activity showed more than 75% viability of cells and significant inhibition in differentiated cells as compared to non-differentiate cells in 3T3-L1 cell line. The extract exhibited the concentration-dependent inhibitory effect with an IC50 value of 689.22 μg/ml.

Conclusions: The extract exhibited significant results for antiadipogenic, antidiabetic and hypolipidemic activity both in-vivo and in-vitro and it may prove to be effective for the treatment of both types of diabetes, i.e. Insulin Dependent Diabetes Mellitus (IDDM) and Noninsulin Dependent Diabetes Mellitus (NIDDM).
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http://dx.doi.org/10.1016/j.jep.2014.06.050DOI Listing
September 2014

In silico identification of viper phospholipaseA2 inhibitors: validation by in vitro, in vivo studies.

J Mol Model 2011 Dec 1;17(12):3063-73. Epub 2011 Mar 1.

Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.

Snake venom, particularly of vipers from the Indian subcontinent, contains Phospholipase A2 (PLA2) as one its constituents which is widely implicated in hemorrhagic, cardiac arrest and death. Development of inhibitors of the protein can facilitate the weakening or annihilation of the venom toxicity and save many human lives. In the present communication, our studies relate to the design and development of structure-based ligands as inhibitors of PLA2 of Viper venom. The study involves the computational approach towards evaluating a library of molecules comprising of natural products, and synthetic molecules through docking studies on the venom protein PDB ID: 1OXL (a dimer, available in the literature). In silico experiments have resulted in the identification of several of them as PLA2 inhibitors. The inhibitory effect of PLA2 by these compounds is attributed to a great extent to their interaction with the residues Phe 46 and Val47 of chain B of the target protein and hence these two residues are identified as the key contributor for the said activity. In order to validate the in silico findings, a selected panel of compounds have been tested by in vitro and in vivo experiments against the venom, which has led to the observance of significant corroboration between the wet lab and in silico findings, validating thereby the in silico approach used in the present study.
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http://dx.doi.org/10.1007/s00894-011-0994-7DOI Listing
December 2011
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