Publications by authors named "Prateek Pathak"

10 Publications

  • Page 1 of 1

Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin-1,2,4-triazole scaffolds.

Arch Pharm (Weinheim) 2021 Mar 3:e2000473. Epub 2021 Mar 3.

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Prayagraj, Uttar Pradesh, India.

Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine-1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods ( H and C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure-activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.
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http://dx.doi.org/10.1002/ardp.202000473DOI Listing
March 2021

Molecular dynamics analysis of phytochemicals from against COVID-19 main protease (M) and human angiotensin-converting enzyme 2 (ACE2).

Biocatal Agric Biotechnol 2021 Mar 27;32:101924. Epub 2021 Jan 27.

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, 211007, India.

The outbreak of COVID-19 created unprecedented strain in the healthcare system. Various research revealed that COVID-19 main protease (M) and human angiotensin-converting enzyme 2 (ACE2) are responsible for viral replication and entry into the human body, respectively. Blocking the activity of these enzymes gives a potential therapeutic target for the COVID-19. The objective of the study was to explore phytochemicals from against SARS-CoV-2 through studies. In this study, 34 phytochemicals of were docked with M and ACE2 through AutoDock Tools-1.5.6 and their binding affinity was studied. Phytochemicals with higher affinity have been chosen for further molecular dynamics simulations to determine the stability with target protein. Molecular dynamics simulations were studied on GROMACS 5.1.4 version. Furthermore, 5-β-glucosyl-7-demethoxy-encecalin (5GDE) and 2-oxocadinan-3,6(11)-dien-12,7-olide (BODO) were found to be potential blockers with excellent binding affinity with Mpro and ACE2 than their native inhibitors remdesivir and hydroxychloroquine respectively. The drug likeness study and pharmacokinetics of the phytoconstituents present in A. adenophora provide an excellent support for the lead drug discovery against COVID-19.
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http://dx.doi.org/10.1016/j.bcab.2021.101924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839396PMC
March 2021

Electronic properties investigation of human dihydrofolate reductase complexes with ligands.

J Biomol Struct Dyn 2020 Dec 21:1-16. Epub 2020 Dec 21.

Department of Chemistry, College of Science, Deanship of Scientific Research, Taif University, Taif, Saudi Arabia.

Despite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. In the focus of this study are complexes of human dihydrofolate reductase (hDHFR) with a series of known inhibitors bound in the active site. Further, a statistical analysis was performed to establish the relationships between a myriad electronic characteristics and IC. The change in total volume and the change of own electrons number of hydrogen atoms in their atomic basins are identified as the descriptors correlating the most with the hDHFR inhibition potency. Additionally, two lipophilic parts of protein (Thr56, Ser59, Ile60 and Ile7, Val8, Ala9) were found, which act as a key factor in decreasing bioactivity. The depth analysis of intermolecular interactions showed that the interactions between water molecules and ligand play a crucial role in hDHFR inhibition. Furthermore, the molecular dynamics simulations were used for deeper understanding of the structural inhibition, each for 50 ns time scale in explicit water conditions. Thus, the AlteQ approach made it possible to determine the factors influencing the activity and evaluate them not only qualitatively, but also quantitatively. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1861985DOI Listing
December 2020

Hybrid Quinazoline 1,3,5-Triazines as Epidermal Growth Factor Receptor (EGFR) Inhibitors with Anticancer Activity: Design, Synthesis, and Computational Study.

ChemMedChem 2021 Mar 1;16(5):822-838. Epub 2020 Dec 1.

Laboratory of Computational Modelling of Drugs, South Ural State University, Chaikovskogo 20A, Chelyabinsk, 454008, Russia.

We report a series of hybrid quinazoline-1,3,5-triazine derivatives as EGFR inhibitors, which were synthesised and tested by using a variety of in vitro, in silico, and in vivo techniques. The derivatives were found to be active against different cancer cell lines and nontoxic against normal ones, with compounds 7 c, 7 d, 7 e, and 7 j being the most potent ones. The derivatives were also evaluated for angiogenesis inhibition potency in chicken eggs, and molecular docking and dynamics simulation studies were carried out to elucidate the fundamental substituent groups essential for their bioactivity. Additionally, a SAR study of the derivatives was performed for future compound optimisation. These studies suggested that the derivatives have a high affinity towards EGFR with favourable pharmacological properties. The most active compound (7 e) was further evaluated for in vivo anticancer activity against DMBA-induced tumours in female Sprague-Dawley rats as well as its effects on plasma antioxidant status, biotransformation enzymes, and lipid profile. The study suggested that 7 e has lead properties against breast cancer and can serve as a starting compound for further development of anti-EGFR compounds.
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http://dx.doi.org/10.1002/cmdc.202000646DOI Listing
March 2021

The study of EGFR-ligand complex electron property relationship with biological activity.

J Biomol Struct Dyn 2020 Sep 8:1-14. Epub 2020 Sep 8.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.

The present investigation grounded on estimation of electron properties of the structures of EGFR proteins-ligand complexes using our laboratory-developed methodology AlteQ approach, which describes the molecular electron density of the complex in space for a certain point in three-dimensional coordinates. Briefly, the system embodies molecular electron density as a sum of Slater's type atomic increments of the molecular system. Further, using this methodology, we calculated different electron characteristics of selected EGFR protein-ligand complexes and established the relationship between different electron properties with their experimental pharmacological activity value (pIC). The study suggested that EGFR inhibitory activity has higher correlation with intermolecular contacts of H with pi-system of aromatic ring between protein and ligands. Therefore, this created model has impact to identify and design potential ligands against EGFR in anticancer drug discovery. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1813629DOI Listing
September 2020

1,2,4-Triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds: A potent ameliorant of carrageenan-induced inflammation by lessening proinflammatory mediators.

Arch Pharm (Weinheim) 2020 Jan 7;353(1):e1900233. Epub 2019 Nov 7.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.

Inflammation acts as an alarming signal for the progression of various biological complications. Various reports in the literature have revealed that heterocycle-containing synthetic compounds have a restorative capability against acute and chronic inflammatory stages. In the current study, we synthesized a series of 1,2,4-triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds and evaluated their impacts against carrageenan-induced paw edema and proinflammatory markers in Wistar rats. Further, 3D QSAR study (three-dimensional quantitative structure-activity relationships), ADMET (absorption, distribution, metabolism, and excretion) profiling, and docking studies were performed to determine the possible mechanism of the action of the derivatives. The study shows that the most active derivatives, 13f and 13g, have optimal logP, a higher anti-inflammatory activity score, and poor metabolism at various sites of cytochrome P450. The docking studies recommended that the synthesized compounds have a similar affinity as the ligands A307, 63X, and S58 to interact with tumor necrosis factor-α, COX-1, and COX-2. So, these molecules will definitely hold a promise for the future drug development initiative.
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http://dx.doi.org/10.1002/ardp.201900233DOI Listing
January 2020

Quinazoline based 1,3,5-triazine derivatives as cancer inhibitors by impeding the phosphorylated RET tyrosine kinase pathway: Design, synthesis, docking, and QSAR study.

Arch Pharm (Weinheim) 2019 Sep 5;352(9):e1900053. Epub 2019 Aug 5.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.

The present research focused on designing a quinazoline skeleton, framed via 1,3,5-triazine derivatives (QBT) through field mapping and alignment studies. The QBT derivatives were synthesized via time- and cost-effective protocol. The 3D-QSAR study, computational physicochemical properties, and ADME calculation of the derivatives were performed to establish the affinity towards the biological system. Molecular docking in the adenosine triphosphate binding site of the RET tyrosine kinase domain (PDB ID: 7IVU) was studied to elucidate vital structural residues necessary for bioactivity. The derivatives were evaluated for anticancer potency against TPC-1 cells (thyroid cancer), MCF-7 cells (breast cancer), and one normal cell line (human foreskin fibroblasts) via 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide assay followed by an in ovo CAM assay. The entire series of derivatives (8a-o) showed mild to significant anticancer potency against the selected cancer cell lines.
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http://dx.doi.org/10.1002/ardp.201900053DOI Listing
September 2019

Evaluation of polyherbal ayurvedic formulation 'Peedantak Vati' for anti-inflammatory and analgesic properties.

J Ethnopharmacol 2019 May 28;235:361-374. Epub 2019 Jan 28.

Drug Discovery and Development Division, Patanjali Research Institute, Haridwar, India.

Ethnopharmacological Relevance: Peedantak Vati (PV) is a polyherbal ayurvedic formulation, which is regularly prescribed by the ayurvedic practitioner for the inflammatory disorders and joints pain in India. It is composed of 23 different herbs and minerals, described in ayurvedic text for their anti-inflammatory and analgesic properties.

Aim Of The Study: To investigate anti-inflammatory and anti-nociceptive potential of 'Peedantak Vati' using in vitro and in vivo methods.

Materials And Methods: In-vitro anti-inflammatory activity of PV was studied by estimating nitric oxide (NO) and LPS-induced pro-inflammatory cytokines IL-6 and TNF-α, using murine macrophage RAW264.7 and human monocyte THP-1 cell lines. PV's anti-inflammatory potential was studied in vivo using carrageenan-induced rat paw edema model. Similarly, anti-nociceptive property of PV was evaluated using hot plate, tail flick, formalin and writhing tests on CD-1 mice. Phytochemical profiling of hydro-alcoholic extract of PV was done using HPLC and HPTLC techniques to identify different marker compounds. These identified marker compounds were confirmed using LC-MS/MS analysis.

Results: In vitro results strongly suggest that, PV significantly (p < 0.001) inhibited NO release and LPS-stimulated pro-inflammatory cytokines IL-6 and TNF-α, in murine RAW264.7 and human THP-1 cells. Further, PV demonstrated significant (p < 0.05) anti-inflammatory activity at different time points after carrageenan injection with maximum effect at 2 h (40.4 ± 5.2% at 400 mg/kg). Similarly, PV significantly (p < 0.05) decreased nociceptive pain, studied using hot plate, tail flick, formalin and writhing tests. Moreover, HPLC and HPTLC methods were developed for the standardization of PV. Five marker phytocompounds viz. rutin, caffeic acid, colchicine, withaferin A and curcumin were identified and quantified by HPLC and HPTLC methods. The presence of these phytoconstituents was confirmed by LC-MS/MS analysis.

Conclusion: The findings of the study strongly suggest that, the polyherbal ayurvedic formulation 'Peedantak Vati' possesses remarkable anti-inflammatory and analgesic property, providing potent alternative for currently available allopathic medicines such as non steroidal anti-inflammatory drugs (NSAIDs).
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http://dx.doi.org/10.1016/j.jep.2019.01.028DOI Listing
May 2019

Quinazoline clubbed 1,3,5-triazine derivatives as VEGFR2 kinase inhibitors: design, synthesis, docking, in vitro cytotoxicity and in ovo antiangiogenic activity.

Inflammopharmacology 2018 Dec 16;26(6):1441-1453. Epub 2018 Apr 16.

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, Uttar Pradesh, 211007, India.

A series of quinazoline clubbed 1,3,5-triazine derivatives (QCT) were synthesized and evaluated for their in vitro anticancer activity against HeLa (human cervical cancer), MCF-7 (human breast cancer cell), HL-60 (human promyelocytic leukemia cell), HepG2 (human Hepatocellular carcinoma cell), and one normal cell line HFF (human foreskin fibroblasts). In vitro assay result encouraged to further move towards in ovo anticancer evaluation using chick embryo. The series of QCT derivatives showed higher anticancer and antiangiogenic activity against HeLa and MCF-7 cell lines. In the series, synthetic molecule 8d, 8l, and 8m displayed significant activity. Further, these results substantiated by docking study on VGFR2. SAR study concluded that the potency of drugs depends on the nature of aliphatic substitution and the heterocyclic ring system.
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http://dx.doi.org/10.1007/s10787-018-0471-3DOI Listing
December 2018

JNK pathway signaling: a novel and smarter therapeutic targets for various biological diseases.

Future Med Chem 2015 27;7(15):2065-86. Epub 2015 Oct 27.

Department of Chemistry, Zakir Husain Delhi College, University of Delhi, New Delhi-110002, India.

JNK pathway regulates various physiological processes including inflammatory responses, cell differentiation, cell proliferation, cell death, cell survival and expression of proteins. Deregulation of JNK is linked with various diseases including neurodegenerative disease, autoimmune disease, diabetes, cancer, cardiac hypertrophy and asthma. Three distinct genes JNK1, JNK2 and JNK3 have been identified as regulator of JNK pathway. JNK1 and JNK2 have broad tissue distribution and play a potential role in insulin resistance, inflammation and cell signaling. JNK3 is predominantly found in the CNS neurons, making it an attractive target for neurodegenerative disorders. In this review, we summarize the evidence supporting JNK as a potent therapeutic target, and small molecules from various chemical classes as JNK inhibitors.
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http://dx.doi.org/10.4155/fmc.15.132DOI Listing
August 2016