Department of Pharmacy
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Item Novel hydrazine derivatives as selective DPP-IV inhibitors: findings from virtual screening and validation through molecular dynamics simulations(Springer, 2014-04) Kumar, GautamThe present study demonstrates and validates the discovery of two novel hydrazine derivatives as selective dipeptidyl peptidase-IV (DPP-IV) inhibitors. Virtual screening (VS) of publicly available databases was performed using virtual screening workflow (VSW) of Schrödinger software against DPP-IV and the most promising hits were selected. Selectivity was further assessed by docking the hits against homology modeled structures of DPP8 and DPP9. Two novel hydrazine derivatives were selected for further studies based on their selectivity threshold. To assess their correct binding modes and stability of their complexes with enzyme, molecular dynamic (MD) simulation studies were performed against the DPP-IV protein and the results revealed that they had a better binding affinity towards DPP-IV as compared to DPP 8 and DPP 9. The binding poses were further validated by docking these ligands with different softwares (Glide and Gold). The proposed binding modes of hydrazines were found to be similar to sitagliptine and alogliptine. Thus, the study reveals the potential of hydrazine derivatives as highly selective DPP-IV inhibitors.Item Pyrazole-pyrazoline as promising novel antimalarial agents: a mechanistic study(Elsevier, 2018-04) Kumar, GautamA series of pyrazole-pyrazoline substituted with benzenesulfonamide were synthesized and evaluated for their antimalarial activity in vitro and in vivo. The compounds were active against both chloroquine (CQ) sensitive (3D7) and CQ resistant (RKL-9) strains of Plasmodium falciparum. Seven compounds (7e, 7i, 7j, 7l, 7m, 7o and 7p) exhibiting EC50 less than 2 μM. A mechanistic study of compound 7o revealed that these compound act through the inhibition of β-hematin. The study indicated that these compounds can serve as lead compounds for further development of potent antimalarial drugs.Item Synthesis of carbohydrazides and carboxamides as anti-tubercular agents(Elsevier, 2018-08) Kumar, GautamA novel series of furan/thiophene carbohydrazides and carboxamides were synthesized and evaluated for anti-TB and cytotoxic activities. All the synthesized compounds were characterized using 1H and 13C NMR and mass spectral techniques. Among the 23 compounds tested for anti-tubercular activity, seven compounds (3e, 3g, 3h, 9b, 9c, 9e and 9h) showed minimum inhibitory concentration value less than 1 μg/mL against Mycobacterium tuberculosis H37Rv and they were found to be non-toxic. Molecular docking and dynamics simulation studies of these compounds with an enzyme enoyl ACP reductase revealed the probable mechanism of action, which is similar to isoniazid. Further, all these tested compounds exhibited good absorption, distribution, metabolism and excretion and drug-likeness in-silico and thus may be considered as potential leads for further drug development.Item Synthesis and biological evaluation of dihydroquinoline carboxamide derivatives as anti-tubercular agents(Elsevier, 2018-09) Kumar, GautamSodium trifluoromethanesulfonate, and glacial acetic acid selectively catalyzed the synthesis of dihydroquinoline via Friedländer annulation. The synthesized dihydroquinoline analogues coupled with different amines by the use of coupling reagent gave dihydroquinoline carboxamide derivatives in moderate to good yields. All the synthesized novel compounds were evaluated for the anti-tubercular activity and cytotoxic activities in vitro. Among tested 30 compounds, two compounds, 8g and 8h showed MIC value of 0.39 and 0.78 μg/mL, respectively against Mycobacterium tuberculosis H37Rv and they were found to be non-toxic. Also these two compounds exhibited good pharmacological properties and oral absorption when studied using in-silico models.Item Indole Derivatives as Anticancer Agents for Breast Cancer Therapy: A Review(Bentham Science, 2016) Sidhu, Jagpreet SinghBreast cancer (BC) is the second most common cause of cancer-related deaths in women throughout the world. Multiple drugs have been approved by US-FDA for breast related malignancies. Frequent emergence of resistances creates the severe need of newer moieties that are free from such problems. Drugs targeting breast cancer have been observed to be based on the multiple mechanisms of action, and various indole based anticancer agents have also been explored. Moreover, indoles have promising anti-cancer potential; there has been the emphasis on the synthesis of indole derivatives to overcome problems faced by existing therapeutic agents. Taking into consideration the above-mentioned facts we have analyzed in detail the possible role of indole based anticancer agents typically for breast related malignancies. This is the first exhaustive review that jointly covers various synthetic anticancer indole derivatives and related signaling pathways by which these derivatives have shown promising anti-breast cancer potential.Item Carbon Dot Based, Naphthalimide Coupled FRET Pair for Highly Selective Ratiometric Detection of Thioredoxin Reductase and Cancer Screening(ACS, 2017-07) Sidhu, Jagpreet SinghThe fluorescence resonance energy transfer (FRET) mechanism has been established between carbon dots (CDs) and naphthalimide to monitor the activity of thioredoxin reductase (TrxR), which is often overexpressed in many cancer cells. The naphthalimide moiety was covalently attached to the surface of CDs through a disulfide linkage. In normal cell conditions (when devoid of high concentrations of TrxR), the CDs act as an energy donor and naphthalimide acts as an acceptor, which establishes the FRET pair as interpreted from the emission at λem = 565 nm, when excited at λex = 360 nm. However, contrary to this, the elevated levels of TrxR cause the breakage of disulfide bonds and consequently abolishes the FRET pair through the release of the naphthalimide moiety from the surface of CDs. This process was studied by monitoring of fluorescence intensity at λem = 565 and 440 nm, when excited at the same wavelength (λex = 360 nm). The TrxR based ratiometric quenching and enhancement of fluorescence intensity offers an interesting opportunity to monitor the enzyme activities and has many advantages over conventional monitoring of fluorescence intensity at a single wavelength to avoid interference of external factors. Fluorescence images of cancer cells in response to the nanosensor were visualized under a confocal microscope. Cytotoxicity study of nanosensor retards the growth of HeLa and MCF-7 cell lines in the presence of visible light. Therefore, the nanosensor also acts as a theranostic agent to diagnose as well as killing of cancer cells.Item Carbon dots as analytical tools for sensing of thioredoxin reductase and screening of cancer cells(RSC, 2018-02) Sidhu, Jagpreet SinghThioredoxin Reductase (TrxR) is a redox regulating enzyme which is predestined for the maintenance of redox homeostasis of mammalian cells. However, the elevated level of TrxR is associated with the progress of various types of tumors and therefore, this is a significant target for the detection of cancer cells. Herein, an easily engineered ‘Turn ON’ fluorescent sensor probe has been synthesized for the detection of TrxR and cell imaging using carbon dots. The emission intensity of fCDs on complexation with Cu2+ ions was drastically quenched. Subsequently, the addition of TrxR to the solution of the fCDs-Cu2+ complex leads to the cleavage of the disulfide bond of the fCDs, which acclaim the release of 3-mercaptopropionic acid. 3-Mercaptopropionic acid, being a strong bi-dentate chelating agent for Cu2+ ions, extracted Cu2+ from the coordination sphere of fCDs and restored the original fluorescence intensity of fCDs. Thus, the probe is operating with a simple process of “ON–OFF” emission switching due to Cu2+ and “OFF–ON” switching with TrxR. The probe has been successfully used for real-time application to monitor TrxR activities in the complex biological system. The fluorescence images of MCF-7 and HeLa cells after incubation with the fCDs-Cu2+ complex were recorded under a confocal laser scanning microscope (CLSM) as a function of time. Enhancement in the emission intensity of cancer cells after 2 h of treatment demonstrates the potential application of the sensor probe for the bioimaging of endogenous TrxR in living cells and screening of cancer cells. Such fluorescent probes will open the door for the development of promising clinical devices for the diagnosis of cancer cells.Item FRET and PET paired dual mechanistic carbon dots approach for tyrosinase sensing(RSC, 2018-05) Sidhu, Jagpreet SinghA dual mechanistic FRET and PET paired ratiometric fluorescence sensor probe has been prepared using carbon dots and naphthalimide fluorophores. The carbon dots are covalently joined with a naphthalimide moiety to develop the FRET phenomenon, which emits at two different wavelengths (i.e., λmax = 440 and 540 nm). However, on catalytic reaction of tyrosinase, the fluorescence emission intensity of the acceptor unit at 540 nm is quenched gradually, owing to the switching on of the PET mechanism; while emission of the donor unit remains significantly unaffected. The probe exhibits high selectivity and specificity towards tyrosinase in complex biological medium with a detection limit of 1.2 U mL−1. Moreover, endogenous images of tyrosinase in B16 cells have been observed under a confocal laser-scanning microscope.Item A highly selective naphthalimide-based ratiometric fluorescent probe for the recognition of tyrosinase and cellular imaging(RSC, 2018) Sidhu, Jagpreet SinghTyrosinase is polyphenolic oxidase enzyme associated with the progression of various diseases. Therefore, for the recognition of tyrosinase, naphthalimide-based ratiometric fluorescent sensor probe was designed and synthesized. 3-Hydroxyphenyl, as the substrate unit for the enzyme, is an important feature of this design, which avoids the interference of other bio-analytes for the recognition of tyrosinase. When the sensor probe was excited at 425 nm, an intense blue emission band emerged at 467 nm. However, upon the addition of tyrosinase to the probe solution, the monophenolic unit oxidized to o-dihydroxy and consequently released the 4-aminonaphthalimide unit. As the oxidation reaction proceeded, the fluorescence emission at 535 nm started to increase gradually with an increase in the concentration of enzyme. Therefore, the sensor probe gives the ratiometric changes via fluorescence spectroscopy. The probe affords high selectivity and sensitivity to tyrosinase with a detection limit of 0.2 U mL−1. Furthermore, live cell images were recorded to assay the endogenous enzyme in A375 cells, which also show a dual color change in the presence of the L3 probe.Item A carbon quantum dot and rhodamine-based ratiometric fluorescent complex for the recognition of histidine in aqueous systems(RSC, 2019-01) Sidhu, Jagpreet SinghHistidine is an essential α-amino acid that plays a crucial role in tissue development and helps in the transmission of metallic ions during biological events. However, an abnormal level of histidine in the body is associated with various physiological conditions such as arthritis, liver cirrhosis, kidney diseases, and asthma. Herein, a unique ratiometric fluorescence sensing system has been developed for the recognition of histidine. The sensing system was developed using carbon quantum dots (CQDs) as an energy donor and a rhodamine 6G derivative (HS30) as an energy acceptor unit. Interestingly, upon the addition of Fe(III) into the mixture of CQDs and HS30, the phenomenon of fluorescence resonance energy transfer (FRET) was observed when excited at 350 nm. The emergence of a strong emission peak at 551 nm on the addition of Fe(III) suggested the formation of a ratiometric fluorescent complex “CQDs–Fe–HS30”. The ratiometric behavior of “CQDs–Fe–HS30” was studied by monitoring fluorescence emissions at 425 nm and 551 nm with an excitation wavelength of 350 nm. Furthermore, “CQDs–Fe–HS30” was employed for the recognition of histidine in an aqueous system. Due to the high affinity of histidine to Fe(III), the addition of histidine to an aqueous solution of “CQDs–Fe–HS30” resulted in the displacement of the Fe(III) cation from the complex, and the simultaneous quenching and enhancement of the emission peaks at 551 nm and 425 nm, respectively, was observed. The developed sensing system was successfully employed for a histidine recovery experiment in human urine samples with satisfactory results. Furthermore, the mixture of CQDs and HS30 was successfully utilized to implement an inhibit logic gate with Fe(III) and histidine as inputs and emission at 551 nm as output.