Publications by authors named "Shaukath Ara Khanum"

47 Publications

Discovery of novel benzophenone integrated derivatives as anti-Alzheimer's agents targeting presenilin-1 and presenilin-2 inhibition: A computational approach.

PLoS One 2022 8;17(4):e0265022. Epub 2022 Apr 8.

Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India.

The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aβ. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265022PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993008PMC
April 2022

Antiproliferative pharmacophore azo-hydrazone analogue BT-1F exerts death signalling pathway targeting STAT3 in solid tumour.

Pharmacol Rep 2022 Apr 10;74(2):353-365. Epub 2022 Jan 10.

Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India.

Background: Anomalous activation of intra-cellular signalling cascades confers neoplastic properties on malignant cells. The JAK2/STAT3 proteins play a pivotal role in the pathogenesis of most of the solid malignancies. The over expression of STAT3 in these tumours results in an evasion of apoptosis and thereby pathogenesis. Hence, strategy to target STAT3 to regress tumour development is an emerging new concept. As an approach, anti-neoplastic drug, Azo-hydrozone analogue, BT-1F with potential anti-proliferative effect was evaluated to demonstrate its capacity to counteract STAT3 signal with mechanistic approach.

Methods: Cell based screening for cytotoxicity was performed through MTT, LDH and Trypan blue. The BT-1F induced anti-clonogenic property by clonogenic assay. The apoptotic capacity was examined by crystal violet staining, flow cytometry, Annexin-FITC, DAPI and TUNEL assay. The altered signalling events were studied using immunoblot. The drug-induced anti-tumour effect was evaluated in an in-vivo solid tumour model and molecular interaction was further validated by in-silico studies.

Results: The BT-1F exerts chemo-sensitivity specifically against EAC and A549 cells without altering its normal counterpart. The anti-proliferative/anti-clonogenic effect was due to the induction of apoptosis through inhibition of STAT3 signal. Eventually downstream signalling proteins p53, Bax, Bad and Bcl-xL were significantly altered. Further in-vivo experimental results validated  in-vitro findings. The computational approaches assures the BT-1F efficiency in binding with STAT3.

Conclusion: Systemic validation of STAT3 target drug, BT-1F in in-vitro, in-silico and in-vivo models has promising strategy for solid cancer treatment.
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http://dx.doi.org/10.1007/s43440-021-00345-wDOI Listing
April 2022

Anti-neoplastic pharmacophore benzophenone-1 coumarin (BP-1C) targets JAK2 to induce apoptosis in lung cancer.

Apoptosis 2022 02 27;27(1-2):49-69. Epub 2021 Nov 27.

Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, 577203, India.

Reigning of the abnormal gene activation associated with survival signalling in lung cancer leads to the anomalous growth and therapeutic failure. Targeting specific cell survival signalling like JAK2/STAT3 nexus has become a major focus of investigation to establish a target specific treatment. The 2-bromobenzoyl-4-methylphenoxy-acetyl hydra acetyl Coumarin (BP-1C), is new anti-neoplastic agent with apoptosis inducing capacity. The current study was aimed to develop antitumor phramacophore, BP-1C as JAK2 specific inhibitor against lung neoplastic progression. The study validates and identifies the molecular targets of BP-1C induced cell death. Cell based screening against multiple cancer cell lines identified, lung adenocarcinoma as its specific target through promotion of apoptosis. The BP-1C is able to induce, specific hall marks of apoptosis and there by conferring anti-neoplastic activity. Validation of its molecular mechanism, identified, BP-1C specifically targets JAK2 phosphorylation, and inhibits its downstream STAT3 signalling pathway to induce cell death. As a consequence, modulation in Akt/Src survival signal and altered expression of interwoven apoptotic genes were evident. The results were reproducible in an in-vivo LLC tumor model and in-ovo xenograft studies. The computational approaches viz, drug finger printing confers, BP-1C as novel class JAK2 inhibitor and molecular simulations studies assures its efficiency in binding with JAK2. Overall, BP-1C is a novel JAK2 inhibitor with experimental evidence and could be effectively developed into a promising drug for lung cancer treatment.
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http://dx.doi.org/10.1007/s10495-021-01699-5DOI Listing
February 2022

Tumor angiogenesis: Current challenges and therapeutic opportunities.

Cancer Treat Res Commun 2021 12;28:100422. Epub 2021 Jun 12.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India. Electronic address:

Angiogenesis plays an important role in the development of cancer since it allows for the delivery of oxygen, nutrients, and growth factors as well as tumor dissemination to distant organs. Inhibition of angiogenesis is an important strategy for the prevention of multiple solid tumors that depend on cutting or at least reducing the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. These drugs are an important part of treatment for some types of cancer. As a stand-alone therapy, inhibition of tumor angiogenesis can arrest or halt tumor growth, but will not eliminate the tumor. Therefore, anti-angiogenic drugs in combinations with another anti-cancer treatment method, like chemotherapy, lead to being critical for optimum cancer patient outcomes. Over the last two decades, investigations have been made to improve the efficacy of anti-angiogenic drugs, recognize their potential in drug interactions, and come up with plausible explanations for possible treatment resistance. This review will offer an overview of the varying concepts of tumor angiogenesis, several important angiogenic factors; focus on the role of anti-angiogenesis strategies in cancer treatment.
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http://dx.doi.org/10.1016/j.ctarc.2021.100422DOI Listing
February 2022

Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia.

Pharmacol Rep 2021 Oct 9;73(5):1344-1360. Epub 2021 Jun 9.

Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, India.

Background: Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression.

Methods: A new series of DPA (7a-t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches.

Results: Initial in vitro anti-proliferative screening of Compounds DPA (7a-t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC value of 4.3 μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways.

Conclusions: Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity.
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http://dx.doi.org/10.1007/s43440-021-00292-6DOI Listing
October 2021

Design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein from Staphylococcus aureus.

Bioinformation 2021 31;17(3):393-403. Epub 2021 Mar 31.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru - 570 005, karnataka, India.

It is of interest to document the design, synthesis, docking, Hirshfeld surface analysis and DFT calculations of 2-methylxanthen-9-with the FtsZ protein (PDB ID: 3VOB) from Staphylococcus aureus for antimicrobial applications. We report the quantitative structure function data in this context.
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http://dx.doi.org/10.6026/97320630017393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131576PMC
March 2021

Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression.

Pharmacol Rep 2021 Oct 26;73(5):1328-1343. Epub 2021 Apr 26.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India.

Background: Hypoxic microenvironment is a common feature of solid tumors, which leads to the promotion of cancer. The transcription factor, HIF-1α, expressed under hypoxic conditions stimulates tumor angiogenesis, favoring HIF-1α as a promising anticancer agent. On the other hand, synthetic Indolephenoxyacetamide derivatives are known for their pharmacological potentiality. With this background here, we have synthesized, characterized, and validated the new IPA (8a-n) analogs for anti-tumor activity.

Methods: The new series of IPA (8a-n) were synthesized through a multi-step reaction sequence and characterized based on the different spectroscopic analysis FT-IR, H, C NMR, mass spectra, and elemental analyses. Cell-based screening of IPA (8a-n) was assessed by MTT assay. Anti-angiogenic efficacy of IPA (8k) validated through CAM, Rat corneal, tube formation and migration assay. The underlying molecular mechanism is validated through zymogram and IB studies. The in vivo anti-tumor activity was measured in the DLA solid tumor model.

Results: Screening for anti-proliferative studies inferred, IPA (8k) is a lead molecule with an IC value of 5 μM. Anti-angiogenic assays revealed the angiopreventive activity through inhibition of HIF-1α and modulation downstream regulatory genes, VEGF, MMPs, and P53. The results are confirmative in an in vivo solid tumor model.

Conclusion: The IPA (8k) is a potent anti-proliferative molecule with anti-angiogenic activity and specifically targets HIF1α, thereby modulates its downstream regulatory genes both in vitro and in vivo. The study provides scope for new target-specific drug development against HIF-1α for the treatment of solid tumors.
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http://dx.doi.org/10.1007/s43440-021-00266-8DOI Listing
October 2021

Synthesis, structural characterization, and DFT studies of anti-cancer drug -(2-Aminophenyl)-2-(4-bromophenoxy)acetamide.

Heliyon 2021 Mar 20;7(3):e06464. Epub 2021 Mar 20.

Department of Engineering Physics, Adichunchanagiri Institute of Technology, Jyothinagara, Chikkamamagaluru 577102, Karnataka, India.

Drug design is an integrated and developing system that portends an era of a novel and safe tailored drugs. It involves studying the effects of biologically active synthetic, semi-synthetic, and natural compounds based on molecular interactions in terms of molecular structure with activated functional groups or its unique physicochemical properties involved. The title compound, -(2-aminophenyl)-2-(4-bromophenoxy) acetamide (), was synthesized in a good yield and characterized by different spectroscopic techniques (H, CNMR, and LC-MS) and finally, the structure was confirmed by X-ray diffraction (XRD) studies. The XRD data confirms that the cryatal structure is orthorhombic with space group of The intermolecular interactions (N-H … O and N-H … Cg) inside the molecule stabilizes the crystal structure. The existence of this intermolecular interactions are computed by the Hirshfeld surfaces (HS) and two-dimensional (2D) fingerprints plot analysis. In addition to this, Energy frame work analysis is performed to quantify the interaction energies between the molecular pairs in a crystal by incorporating new version of CrystalExplorer17 using the energy model of HF/3-21G. Also to calculate the HOMO and LUMO energies, DFT calculations were carried out.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020429PMC
March 2021

Molecular docking and synthesis of caffeic acid analogous and its anti-inflammatory, analgesic and ulcerogenic studies.

Bioorg Med Chem Lett 2021 02 13;33:127743. Epub 2020 Dec 13.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru, Karnataka, India. Electronic address:

A series of caffeic acid (CA) derivatives 7a-j were synthesized via etherification and coupling action and their chemical structures were elucidated spectroscopically. Motivated by the various biological activities displayed by CA derivatives such as anti-inflammatory, antiviral, anticancer and antioxidant and also based on its extensively consumption in the human diet. In the present work, the newly synthesized compounds 7a-j were evaluated for anti-inflammatory and analgesic action and most of them exerted comparable activity to the reference compound celecoxib. Further, ulcer indexes for the most active compounds were calculated and most of them showed less ulcerogenic effect than the reference drug. Among the title series 7a-j, compounds 7f and 7g with electron withdrawing bromo and chloro group respectively, at the para position of the phenoxy ring was showed good activity compared to all other compounds. Interestingly, the COX-I/COX-II activity ratio of potent compounds 7f and7g showed an almost equal inhibitory effect on both isoenzymes. Further, molecular docking studies have been performed for the potent compounds which showed statistically significant result.
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http://dx.doi.org/10.1016/j.bmcl.2020.127743DOI Listing
February 2021

Design, synthesis and molecular docking of benzophenone conjugated with oxadiazole sulphur bridge pyrazole pharmacophores as anti inflammatory and analgesic agents.

Bioorg Chem 2019 11 26;92:103220. Epub 2019 Aug 26.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru, Karnataka, India. Electronic address:

The prostaglandins (PG) a group of physiologically active lipid compounds having diverse hormone like effects are important mediators of the body's response to pain and inflammation, and are formed from essential fatty acids found in cell membranes. This reaction is catalyzed by cyclooxygenase, a membrane associated enzyme occurring in two isoforms, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of COX. In view of this, a series of novel benzophenones conjugated with oxadiazole sulphur bridge pyrazole moiety 8a-l were designed, synthesized, characterized and subsequently evaluated for anti-inflammatory and analgesic property. The investigation of novel analogues 8a-l for potential anti-inflammatory activity showed high levels of COX-1 and COX-2 inhibitory activity. Among the series, compound 8i with electron withdrawing fluoro group at the para position of the benzoyl ring of benzophenone was characterized by highest IC values for both COX-1 and COX-2 inhibition, which is comparable to the standard drug. Further, molecular docking studies have been performed for the potent compound.
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http://dx.doi.org/10.1016/j.bioorg.2019.103220DOI Listing
November 2019

Synthesis of coumarin analogs appended with quinoline and thiazole moiety and their apoptogenic role against murine ascitic carcinoma.

Biomed Pharmacother 2019 Apr 27;112:108707. Epub 2019 Feb 27.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru, 570005, Karnataka, India. Electronic address:

The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, H NMR, C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 μM), tryphan blue (15.6 μM) and LDH (14.2 μM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.
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http://dx.doi.org/10.1016/j.biopha.2019.108707DOI Listing
April 2019

Correction: The critical role of novel benzophenone analogs on tumor growth inhibition targeting angiogenesis and apoptosis.

Medchemcomm 2018 04 10;9(4):744. Epub 2018 Apr 10.

Department of Chemistry , Yuvaraja's College , University of Mysore , Mysore -570005 , Karnataka , India . Email: ; ; Tel: +91 99018 88755.

[This corrects the article DOI: 10.1039/C7MD00593H.].
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http://dx.doi.org/10.1039/c8md90018cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144809PMC
April 2018

The critical role of novel benzophenone analogs on tumor growth inhibition targeting angiogenesis and apoptosis.

Medchemcomm 2018 Apr 15;9(4):639-656. Epub 2018 Feb 15.

Department of Chemistry , Yuvaraja's College , University of Mysore , Mysore -570005 , Karnataka , India . Email: ; ; Tel: +91 99018 88755.

In modern biology, one of the major topics of importance is progress in anti-cancer drugs with specific targets. The angiopreventive and tumor inhibition activities of novel synthetic benzophenone analogs have been investigated intensively and explored in a very systematic way. Novel benzophenone analogs ( and ) substituted with methyl, chloro and fluoro groups at different positions on an identical chemical backbone and incorporating variations in the number of substituents have been synthesized in a multistep process and characterized. In this study, we further evaluate the newly synthesized compounds for their cytotoxic and anti-proliferative effects against A549, HeLa and MCF-7 cells. The potent lead compound was further assessed for anti-angiogenic effects. Through the structure-activity relationship, we found that an increase in the number of methyl, chloro and fluoro groups in a benzophenone ring on compound resulted in higher potency compared to other compounds. Tumor inhibition was notably promoted, and this was reflected in effects on neovessel formation in systems, such as the CAM. Compound interacts with rVEGF through hydrogen bonds , thereby down-regulating the expression of VEGF in angiogenesis. From our investigation, it is suggested on the basis of clonogenesis and cell migration assays that compound has the potency to exhibit prolonged activity against cancer progression, through cell cycle arrest at the G2/M phase. In addition, compound inhibits A549 cells through caspase-activated DNase-mediated apoptosis.
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http://dx.doi.org/10.1039/c7md00593hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072443PMC
April 2018

Synthesis and amelioration of inflammatory paw edema by novel benzophenone appended oxadiazole derivatives by exhibiting cyclooxygenase-2 antagonist activity.

Biomed Pharmacother 2018 Jul 7;103:1446-1455. Epub 2018 May 7.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore, 570005 Karnataka, India. Electronic address:

Ten new 2(4-hydroxy-3-benzoyl) benzamide-5-phenyl-1,3,4-oxadiazole derivatives (10a-j) were synthesized by coupling 3-benzoyl-4-hydroxybenzoic acid (5) with 2-amino-5-phenyl-1,3,4-oxadiazoles (9a-j). The structures of these compounds were confirmed by IR, H, C NMR, and mass spectra, and also by elemental analyses. The anti-inflammatory activity of the compounds 10a-j were investigated by screening them against human red blood cells (HRBC) in-vitro. The results reveal that among this series, compound 10j with hydroxy substituent, particularly at the ortho position of the phenyl ring attached to the 5th carbon atom of the oxadiazole ring possess significant membrane stabilizing activity in comparison with the control. Further, in-vivo chick chorioallantoic membrane (CAM) and rat corneal anti-angiogenesis assays were performed to assess the effect of compound 10j on endothelial cell migration. This confirmed that compound 10j inhibits the proliferation of endothelial cells. Anti-inflammatory studies detected the amelioration of carrageen induced rat hind paw edema. Further in-vivo and in-silico approaches revealed the inhibition of inflammatory marker enzyme cyclooxygenase-2 (Cox-2) and myleoperoxidase (MPO). The study reports that the compound 10j effectively act against the inflammatory mediated anti-angiogenic disorders which could be translated into a new drug in future.
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http://dx.doi.org/10.1016/j.biopha.2018.04.167DOI Listing
July 2018

The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death.

Eur J Med Chem 2018 Jan 4;143:1826-1839. Epub 2017 Nov 4.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore 570005, Karnataka, India. Electronic address:

Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8 were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC value of ˜ 13 μM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis.
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http://dx.doi.org/10.1016/j.ejmech.2017.10.082DOI Listing
January 2018

Design and synthesis of conjugated azo-hydrazone analogues using nano BF·SiO targeting ROS homeostasis in oncogenic and vascular progression.

Biomed Pharmacother 2017 Nov 12;95:419-428. Epub 2017 Sep 12.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysore, Karnataka, India. Electronic address:

Disrupted redox balance is implicated in multiple pathologies including malignant progression and tumor angiogenesis. In this investigation, we report the design and development of novel and effective ROS detoxifying azo-hydrazone molecules targeting malignant pathologies and neoangiogenesis. A series of azo-derivatives conjugated to hydrazones moieties (9a-j) were synthesized using Nano BF·SiO. The compounds (9a-j) were screened for in-vitro antioxidant and lipid peroxidation inhibitory activity. Among the series 9a-j, compound 9f potently quenched biologically relevant radicals such as superoxide and hydrogen peroxide which emerged as the lead ROS detoxifying molecules. Compound 9f potently inhibited the proliferative capability of Daltons Lymphoma Ascites (DLA) tumor cells in-vivo in dose dependent manner. Regressed tumor progression was correlated with pronounced endogenous antioxidant enzyme superoxide dismutase and catalase in-vivo. Also, ROS levels were severely suppressed in 9f treated mice as assessed by lapsed lipid peroxidation. Altered enzymic and ROS levels in-vivo by 9f were implicated in suppressed VEGF secretion leading to regressed tumor neovasculature and tumor growth. Considering together, it is evident that the synthetic azo-hydrazone analogue 9f with potent ROS scavenging efficacy inhibits tumor progression and neo-angiogenesis.
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http://dx.doi.org/10.1016/j.biopha.2017.08.076DOI Listing
November 2017

The anti-invasive role of novel synthesized pyridazine hydrazide appended phenoxy acetic acid against neoplastic development targeting matrix metallo proteases.

Biomed Pharmacother 2017 Nov 12;95:375-386. Epub 2017 Sep 12.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore, 570005 Karnataka, India. Electronic address:

Neoplastic metastasis is a major process where tumor cells migrate from the primary tumor and colonize at other parts of our body to form secondary tumor. Cancer incidences are rising and novel anti-neoplastic compounds with new mechanism of actions are essential for preventing cancer related deaths. In the current examination, a novel series of pyridazine analogues 6a-l was synthesized and evaluated against metastatic neoplastic cells. Experimental data postulated compound 6j has potential cytotoxic efficacy with prolonged activity against various cancer cells, including A549, HepG2, A498, CaSki and SiHa cells. Moreover, compound 6j arrests the A549 migration and invasions markedly by counteracting matrix metalloproteinase (MMP)-2 and MMP-9 expressions. Also, compound 6j proved its potentiality against Dalton's solid lymphoma progression in-vivo by abridging MVD and MMP expressions. Compound 6j interacts with MMP-2 and MMP-9 by H- bond in-silico, thereby down regulates the MMPs action in tumourigenesis. Altogether, we concluded that compound 6j down regulates MMP-2 and MMP-9 and thereby impairs metastatic cancer cell migration and invasions which can be translated into a potent anti-neoplastic agent.
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http://dx.doi.org/10.1016/j.biopha.2017.08.105DOI Listing
November 2017

Synthesis of novel morpholine conjugated benzophenone analogues and evaluation of antagonistic role against neoplastic development.

Bioorg Chem 2017 04 18;71:55-66. Epub 2017 Jan 18.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore 570005, Karnataka, India. Electronic address:

A series of novel 4-benzyl-morpholine-2-carboxylic acid N'-[2-(4-benzoyl-phenoxy)-acetyl]-hydrazide derivatives 8a-j has been synthesized from (4-hydroxy-aryl)-aryl methanones through a multi-step reaction sequence and then evaluated for anti-proliferative activity in vitro against various types of neoplastic cells of mouse and human such as DLA, EAC, MCF-7 and A549 cells. From the cytotoxic studies and structural activity relationship of compounds 8a-j, it is clear that methyl group on the B ring of benzophenone is essential for antiproliferative activity and bromo at ortho position (compound 8b) and methyl at para position (compound 8f) on A ring of benzophenone are significant for extensive anti-mitogenic activity. Investigation on clonogenesis and Fluorescence-activated cell sorting suggests that compounds 8b and 8f have the potency to exhibit the prolonged activity with cell cycle arrest on G2/M phase against cancer progression. Further, the compounds 8b and 8f inhibit murine ascites lymphoma through caspase activated DNase mediated apoptosis.
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http://dx.doi.org/10.1016/j.bioorg.2017.01.011DOI Listing
April 2017

A tumoural angiogenic gateway blocker, Benzophenone-1B represses the HIF-1α nuclear translocation and its target gene activation against neoplastic progression.

Biochem Pharmacol 2017 Feb 9;125:26-40. Epub 2016 Nov 9.

Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, India. Electronic address:

Hypoxia is an important module in all solid tumours to promote angiogenesis, invasion and metastasis. Stabilization and subsequent nuclear localization of HIF-1α subunits result in the activation of tumour promoting target genes such as VEGF, MMPs, Flt-1, Ang-1 etc. which plays a pivotal role in adaptation of tumour cells to hypoxia. Increased HIF-α and its nuclear translocation have been correlated with pronounced angiogenesis, aggressive tumour growth and poor patient prognosis leading to current interest in HIF-1α as an anticancer drug target. Benzophenone-1B ([4-(1H-benzimidazol-2-ylmethoxy)-3,5-dimethylphenyl]-(4-methoxyphenyl) methanone, or BP-1B) is a new antineoplastic agent with potential angiopreventive effects. Current investigation reports the cellular biochemical modulation underlying BP-1B cytotoxic/antiangiogenic effects. Experimental evidences postulate that BP-1B exhibits the tumour specific cytotoxic actions against various cancer types with prolonged action. Moreover BP-1B efficiently counteracts endothelial cell capillary formation in in-vitro, in-vivo non-tumour and tumour angiogenic systems. Molecular signaling studies reveal that BP-1B arrests nuclear translocation of HIF-1α devoid of p42/44 pathway under CoCl induced hypoxic conditions in various cancer cells thereby leading to abrogated HIF-1α dependent activation of VEGF-A, Flt-1, MMP-2, MMP -9 and Ang-1 angiogenic factors resulting in retarded cell migration and invasions. The in-vitro results were reproducible in the reliable in-vivo solid tumour model. Taken together, we conclude that BP-1B impairs angiogenesis by blocking nuclear localization of HIF-1α which can be translated into a potent HIF-1α inhibitor.
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http://dx.doi.org/10.1016/j.bcp.2016.11.009DOI Listing
February 2017

BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation.

Angiogenesis 2017 Feb 14;20(1):55-71. Epub 2016 Oct 14.

Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India.

Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.
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http://dx.doi.org/10.1007/s10456-016-9528-3DOI Listing
February 2017

Evaluation of adhesive and anti-adhesive properties of Pseudomonas aeruginosa biofilms and their inhibition by herbal plants.

Iran J Microbiol 2016 Apr;8(2):108-19

Toxinology/Toxicology and Drug Discovery Unit, Center for Emerging Technologies, Jain Global Campus, Jain University, Kanakapura Taluk, Bangalore-562 112, Karnataka, India.

Background And Objectives: Adhesion and colonization are prerequisites for the establishment of bacterial pathogenesis. The biofilm development of Pseudomonas aeruginosa was assessed on adhesive surfaces like dialysis membrane, stainless steel, glass and polystyrene.

Materials And Methods: Microtiter plate biofilm assay was performed to assess the effect of nutrient medium and growth parameters of P. aeruginosa. Further, its growth on adhesive surfaces namely hydrophilic (dialysis membrane) and hydrophobic (polystyrene plate, square glass and stainless steel coupon) was assessed. The exopolysaccharide (EPS) was quantified using ruthenium red microplate assay and microscopic analysis was used to observe P. aeruginosa biofilm architecture. The anti-biofilm activity of herbal extracts on mature P. aeruginosa was performed.

Results: The formation of large scale biofilms on dialysis membrane for 72 h was proved to be the best surface. In microscopic studies, very few exopolysaccaride fibrils, indicating a rather loose matrix was observed at 48 h. Further, thick exopolysaccaride, indicated higher adhesive properties at 72 h which is evident from ruthenium red staining. Among the plant extract used, Justicia wynaadensis leaf and Aristolochia indica (Eswari) root extract showed significant reduction of anti-biofilm activity of 0.178 OD and 0.192 OD in inhibiting mature biofilms at 0.225 OD respectively, suggesting the possible use of these extracts as efficient anti-adhesive and biofilm-disrupting agents with potential applications in controlling biofilms on surfaces.

Conclusion: Our study facilitates better understanding in the development of P. aeruginosa biofilms on different food processing and clinical surfaces ultimately taking care of food safety and hygiene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906717PMC
April 2016

Design and synthesis of diamide-coupled benzophenones as potential anticancer agents.

Eur J Med Chem 2016 Jun 18;115:342-51. Epub 2016 Mar 18.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysore, Karnataka, India. Electronic address:

A series of diamide-coupled benzophenone, 2-(4-benzoyl-phenoxy)-N-{2-[2-(4-benzoyl-phenoxy)-acetylamino]-phenyl}-acetamide analogues (9a-l) were synthesized by multistep reactions and all compounds were well characterized. Among the series (9a-l), compound 9k with three methyl groups at ortho position in rings A, B, and D and bromo group at the para position in ring E was selected as a lead compound by screening through multiple cancer cell types by in-vitro cytotoxic and antiproliferative assay systems. Also, the cytotoxic nature of the compound 9k resulted the regression of the tumor growth in-vivo, which could be due to decreased vascularisation in the peritoneum lining of the mice which regress the tumor growth. The results were reconfirmed in-vivo chorioallantoic membrane model which indicates a scope of developing 9k into potent anticancer drug in near future.
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http://dx.doi.org/10.1016/j.ejmech.2016.03.040DOI Listing
June 2016

Synthesis and biological evaluation of salicylic acid conjugated isoxazoline analogues on immune cell proliferation and angiogenesis.

Eur J Med Chem 2016 May 24;114:153-61. Epub 2016 Feb 24.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore, 570005 Karnataka, India. Electronic address:

Mitogenicity is the ability of the natural or synthetic compounds to induce cell division or proliferation. A series of salicylic acid derivatives containing isoxazoline moiety (8a-j) were synthesized and their immunopharmacological activities targeting lymphocyte proliferation and angiogenesis were evaluated. The compounds 8a-j mitogenicity were investigated on immunological cells that include human peripheral blood lymphocytes and murine splenocytes in-vitro. The results implicate that among the series of 8a-j, compound 8e showed a potent proliferative response on both human and murine lymphocytes. The proliferative index of the compound 8e was comparable to the reference mitogen Con A and mitogenecity is due to increased secretion IL-2. In -vivo CAM and rat corneal angiogenesis assays were performed to assess the compound's effect on endothelial cell migration and proliferation which inferred that 8e also induces the proliferation of endothelial cells. The study reports the synthetic immunostimulatory and pro-angiogenic activity of novel mitogen 8e which could be translated into new drug in future.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.052DOI Listing
May 2016

Synthesis and an angiolytic role of novel piperazine-benzothiazole analogues on neovascularization, a chief tumoral parameter in neoplastic development.

Bioorg Chem 2016 Apr 21;65:110-7. Epub 2016 Feb 21.

Department of Chemistry, Yuvaraja's College, University of Mysore, Karnataka, India. Electronic address:

A novel series of benzoic acid N'-[2-(4-benzothiazol-2-yl-piperazin-1-yl)-acetyl]-hydrazides 6a-j were synthesized and characterized by IR, (1)H, (13)C NMR, elemental and mass spectral analyses. The in-vitro cytotoxicity and cell viability assay of the synthesized compounds 6a-j were evaluated against Dalton's lymphoma ascites (DLA) cells. Our results showed that compound 6c with a bromo group on phenyl ring has showed promising antiproliferative efficacy. Further investigation of compound 6c on in-vivo treatment model depicts the increased tumor suppression through inhibition of angiogenesis.
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http://dx.doi.org/10.1016/j.bioorg.2016.02.006DOI Listing
April 2016

Synthesis and antiproliferative activity of benzophenone tagged pyridine analogues towards activation of caspase activated DNase mediated nuclear fragmentation in Dalton's lymphoma.

Bioorg Chem 2016 Apr 2;65:73-81. Epub 2016 Feb 2.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore 570005, Karnataka, India. Electronic address:

A series of benzophenones possessing pyridine nucleus 8a-l were synthesized by multistep reaction sequence and evaluated for antiproliferative activity against DLA cells by in vitro and in vivo studies. The results suggested that, compounds 8b with fluoro group and 8e with chloro substituent at the benzoyl ring of benzophenone scaffold as well as pyridine ring with hydroxy group exhibited significant activity. Further investigation in mouse model suggests that compounds 8b and 8e have the potency to activate caspase activated DNase (endonuclease) which is responsible for DNA fragmentation, a primary hallmark of apoptosis and thereby inhibits the Dalton's lymphoma ascites tumour growth.
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http://dx.doi.org/10.1016/j.bioorg.2016.02.001DOI Listing
April 2016

Synthesis of oxadiazole-morpholine derivatives and manifestation of the repressed CD31 Microvessel Density (MVD) as tumoral angiogenic parameters in Dalton's Lymphoma.

Bioorg Chem 2015 Jun 1;60:136-46. Epub 2015 May 1.

Department of Chemistry, Yuvaraja's college, University of Mysore, Mysore 570005, Karnataka, India. Electronic address:

A series of oxadiazole derivatives possessing morpholine 6a-l were synthesized by nucleophilic substitution reaction of key intermediates [1,3,4]-oxadiazole-2-thiol derivatives 5a-l with 4-(2-chloroethyl) morpholine. Compounds 6a-l were evaluated for their in vitro and in vivo antitumor potential in Dalton's Lymphoma Ascites (DLA) tumor cells. Among 6a-l series, compound 6a with concentration ∼8.5μM have shown extensive cytotoxicity in vitro and 85% reduction in tumor volume in vivo, attributing an excellent anti-proliferative capability towards the cancer cells. Compound 6a has extensively inhibited the Microvessel Density (MVD) or tumoral neovasculature which was evident from the CD31 immuno staining and peritoneal H&E staining. The major reason for the antiproliferative activity of compound 6a was due to the repression of tumor vasculature.
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http://dx.doi.org/10.1016/j.bioorg.2015.04.008DOI Listing
June 2015

Synthesis and evaluation of in vitro antimicrobial activity of novel 2-[2-(aroyl)aroyloxy]methyl-1,3,4-oxadiazoles.

Bioorg Khim 2014 May-Jun;40(3):357-62

Synthetic pathway of the ten novel 2-[2-(aroyl)aroyloxy]methyl-1,3,4-oxadiazoles as new potential antimicrobial agents is illustrated. Intramolecular cyclization of 2-(2-aroylaryloxy) aceto hydrazides to 2-[2-(aroyl)aroyloxy]methyl-1,3,4-oxadiazoles was achieved with triethyl orthoformate in good yields. The compounds were characterized by IR, 1H NMR, mass spectra and by means of CHN analysis. The target compounds were tested for their in vitro antimicrobial activity against representative strains by disc diffusion method and micro dilution methods. Several compounds showed antimicrobial activity comparable with or higher than the standard drugs.
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June 2015

Synthesis and evaluation of in vitro antioxidant properties of novel 2,5-disubstituted 1,3,4-oxadiazoles.

Bioorg Khim 2014 Mar-Apr;40(2):226-33

2,5-Disubstituted 1,3,4-oxadiazole compounds are one of the most attractive heterocyclic compounds for researchers due to their biological activities. In the undertaken research, a number of potential 2,5-disubstituted 1,3,4-oxadiazole analogues were synthesized through multi step reaction and characterized by FT-IR, 1H NMR, mass spectra, and also by elemental analysis. Further benzophenone tagged indole acetohydrazides and 2,5-disubstituted 1,3,4-oxadiazoles were evaluated for antioxidant potential, through different in vitro models such as DPPH, nitric oxide and hydrogen peroxide methods. In the series of compounds some of them had shown good to moderate in vitro antioxidant potential compare to the standard drug ascorbic acid in all the above three methods.
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http://dx.doi.org/10.1134/s1068162014020083DOI Listing
June 2015

Synthesis and evaluation of novel benzophenone-thiazole derivatives as potent VEGF-A inhibitors.

Eur J Med Chem 2014 Nov 27;87:274-83. Epub 2014 Sep 27.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore 570005, Karnataka, India. Electronic address:

A series of 2-(4-benzoyl-phenoxy)-N-(4-phenyl-thiazol-2-yl)-acetamides (10a-n) were synthesized by multistep reaction sequence and all the compounds were well characterized for structural elucidation. The in vitro cytotoxicity of compounds 10a-n was evaluated against EAC and DLA cell lines using trypan blue dye exclusion method. Further MTT assay and LDH release assay, followed by in vivo studies on murine model were also evaluated. The compound 10h with a methyl and fluoro groups at benzophenone moiety and methoxy group at phenyl ring was in a leading position to exhibit the promising antiproliferative effect through translational VEGF-A inhibition.
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http://dx.doi.org/10.1016/j.ejmech.2014.09.069DOI Listing
November 2014

Synthesis, characterization, biological and catalytic applications of transition metal complexes derived from Schiff base.

Bioorg Med Chem Lett 2014 Aug 23;24(15):3559-64. Epub 2014 May 23.

Department of Chemistry, Yuvaraj's College (Autonomous), University of Mysore, Mysore 570 005, Karnataka, India. Electronic address:

A novel series of Cu(II), Ni(II), Zn(II), Co(II), and Cd(II) complexes have been synthesized from the Schiff base. Structural features were determined by analytical and spectral techniques like IR, (1)H NMR, UV-vis, elemental analysis, molar electric conductibility, magnetic susceptibility and thermal studies. The complexes are found to be soluble in dimethylformamide and dimethylsulfoxide. Molar conductance values in dimethylformamide indicate the non-electrolytic nature of the complexes. Binding of synthesized complexes with calf thymus DNA (CT DNA) was studied. There is significant binding of DNA in lanes 2, 3, and 5. Lanes 4 and 6 are showing more florescence when compared to the control indicating that these molecules are strongly bound to the DNA by inserting themselves between the two stacked base pairs and exhibiting their original property of fluorescence. Angiogenesis study has revealed that the compounds B-2, B-4 and B-5 have potent antitumor efficacy and activation of antiangiogenesis could be one of the possible underlying mechanisms of tumor inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2014.05.046DOI Listing
August 2014
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