Publications by authors named "Vikramdeep Monga"

28 Publications

  • Page 1 of 1

An insight into the medicinal attributes of berberine derivatives: A review.

Bioorg Med Chem 2021 May 2;38:116143. Epub 2021 Apr 2.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga-142001, Punjab, India. Electronic address:

In the last few decades, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding perpetually. Berberine, with remarkable therapeutic diversity, is a plant derived isoquinoline alkaloid which is widely used as a traditional medicine in China. Berberine has been tackled as a fascinating pharmacophore to make great contributions to the discovery and development of new therapeutic agents against variegated diseases. Despite its tremendous therapeutic potential, clinical utility of this alkaloid was significantly compromised due to undesirable pharmacokinetic properties. To overcome this limitation, several structural modifications were performed on this scaffold to improve its therapeutic efficacy. The collective efforts of the community have achieved the tremendous advancements, bringing berberine to clinical use and discovering new therapeutic opportunities by structural modifications on the berberine scaffold. In this review, recent advancements in the medicinal chemistry of berberine and its derivatives in the last few years (2016-2020) have been compiled to represent inclusive data associated with various biological activities of this alkaloid. The comprehensive structure-activity relationship studies along with molecular modelling and mechanistic studies have also been summarized. This article would be highly helpful for the scientific community to get better insight into medicinal research of berberine and become a compelling guide for the rational design of berberine based compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2021.116143DOI Listing
May 2021

Recent advancements in the medicinal chemistry of bacterial type II topoisomerase inhibitors.

Bioorg Chem 2020 11 3;104:104266. Epub 2020 Sep 3.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga 142001, Punjab, India. Electronic address:

Replication proteins are sought as a potential targets for antimicrobial agents. Despite their promising target characteristics, only topoisomerase II inhibitors targeting DNA gyrase and/or topoisomerase IV have reached clinical use. Topoisomerases are the enzymes that are essential for cellular functions and various biological activities. A wide range of natural and synthetic compounds have been identified as potential topoisomerase inhibitors but the resistance is most commonly found in these drugs. The emergence of FQ resistance has increased the need for the development of novel topoisomerase inhibitors with efficacy and high potency against FQ-resistant strains. Besides structural modifications of existing FQ scaffolds, novel non-quinolone topoisomerase II inhibitors, known as novel bacterial topoisomerase inhibitors, have been developed which showed remarkable inhibitory activity against DNA gyrase/topoisomerase IV or both with an improved spectrum of antibacterial potency including drug-resistant strains. This review aims to summarize various recent advancements in the medicinal chemistry of topoisomerase inhibitors with the following objectives: (1) To represent inclusive data on types of topoisomerases and various marketed topoisomerase inhibitors as drugs; (2) To discuss the recent advances in the medicinal chemistry of various topoisomerase inhibitors (DNA gyrase and topo IV) belonging to different structural classes as potential antibacterial agents; (3) To summarizes the structure activity relationship (SAR) including in silico and mechanistic studies to afford ideas and to provide focused direction for the development of new chemical entities which are effective against drug-resistant bacterial pathogens and biofilms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.104266DOI Listing
November 2020

Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors.

Eur J Med Chem 2021 Jan 15;209:112923. Epub 2020 Oct 15.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga, 142001, Punjab, India. Electronic address:

Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and bicarbonate; a reaction which plays a crucial role in many physiological and pathological processes. Carbonic anhydrase is present in human (h) with sixteen different isoforms ranging from hCA I-hCA XV. All these isoforms are widely distributed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of carbonic anhydrase have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, hemolytic anemia, epilepsy, obesity, and cancer. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.) are not selective causing the undesirable side effects. One of the major hurdles in the design and development of carbonic anhydrase inhibitors is the lack of balanced isoform selectivity which thrived to new chemotypes. In this review, we have compiled the recent strategies of various researchers related to the development of carbonic anhydrase inhibitors belonging to different structural classes like pyrimidine, pyrazoline, selenourea, isatin, indole, etc. This review also summarizes the structure-activity relationships, analysis of isoform selectivity including mechanistic and in silico studies to afford ideas and to provide focused direction for the design and development of novel isoform-selective carbonic anhydrase inhibitors with therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112923DOI Listing
January 2021

Recent advancements in the development of bioactive pyrazoline derivatives.

Eur J Med Chem 2020 Nov 29;205:112666. Epub 2020 Jul 29.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, GT Road, Ghal Kalan, Moga, 142001, Punjab, India. Electronic address:

Pyrazolines remain privileged heterocycles in drug discovery. 2-Pyrazoline scaffold has been proven as a ubiquitous motif which is present in a number of pharmacologically important drug molecules such as antipyrine, ramifenazone, ibipinabant, axitinib etc. They have been widely explored by the scientific community and are reported to possess wide spectrum of biological activities. For combating unprecedented diseases and worldwide increasing drug resistance, 2-pyrazoline has been tackled as a fascinating pharmacophore to generate new molecules with improved potency and lesser toxicity along with desired pharmacokinetic profile. This review aims to summarizes various recent advancements in the medicinal chemistry of pyrazoline based compounds with the following objectives: (1) To represent inclusive data on pyrazoline based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical developments; (2) To discuss recent advances in the medicinal chemistry of pyrazoline derivatives with their numerous biological significances for the eradication of various diseases; (3) Summarizes structure-activity relationships (SAR) including in silico and mechanistic studies to afford ideas for the design and development of novel compounds with desired therapeutic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112666DOI Listing
November 2020

Design, synthesis and neuropharmacological evaluation of new 2,4-disubstituted-1,5-benzodiazepines as CNS active agents.

Bioorg Chem 2020 08 16;101:104010. Epub 2020 Jun 16.

Department of Pharmaceutical Chemistry, Rajendra Institute of Technology & Sciences, Sirsa 125055, Haryana, India; Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, GT Road, Moga 142001, Punjab, India. Electronic address:

Benzodiazepines (BZDs) represent a class of privilege scaffold in the modern era of medicinal chemistry as CNS active agents and BZD based drugs are used to treat different psychotic disorders. Inspired from the therapeutic potential of BZDs as promising CNS active agents, in the present work three different series of 1,5-benzodiazepines bearing various substitutions at position 2 and 4 of the benzodiazepine core were synthesized by condensing different substituted chalcones with o-phenylenediamine in the presence of piperidine as a base catalyst. Structural characterization of title compounds was done by using various analytical techniques such as IR, NMR, elemental analysis and mass spectral data. All the synthesized compounds (9a-d, 10a-e and 11a-c) were subjected to in vivo neuropharmacological studies to evaluate their CNS depressant and antiepileptic activity. Results of in vivo evaluation data showed that analogue 11b exhibited potent CNS depressant activity which was comparable to the standard drug diazepam. Compounds 10b and 10c displayed significant antiepileptic activity however they were less potent than the standard drug phenobarbitone. Molecular docking studies were performed using MOE software to find the interaction pattern and binding mode at the GABAA receptor (PDB Id: 6HUP). The results of the docking studies were in good agreement with the observed in vivo activity and revealed the satisfactory binding mode of the compounds within the binding site of the protein. The docking scores for the most promising candidates 10c, 11b and Diazepam were found to be -9.18, -9.46 and -9.88, respectively. Further, the compounds showed compliance with the Lipinski's 'rule of five' and exhibited favourable drug-likeness scores. The identified leads can be explored further for the design and development of new BZD based psychotropic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.104010DOI Listing
August 2020

Recent advancements in the development of heterocyclic anti-inflammatory agents.

Eur J Med Chem 2020 Aug 16;200:112438. Epub 2020 May 16.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, G.T Road, Moga, Punjab, 142001, India. Electronic address:

Most of the anti-inflammatory drugs in clinical practice are becoming outdated owing to their potential side and adverse effects. These are found to be highly unsafe for long term use. Thus, since last few years, new anti-inflammatory agents are being developed and number of them are in advanced stages of clinical trials. Heterocyclic molecules have gained great attention of chemists due to their similarity to different biological precursors. In the current review, we have highlighted the recent developments (2015 onwards) in designing and synthesis of various heterocyclic anti-inflammatory molecules along with detailed SAR studies. The principal objective of this review is to provide a profound overview of the recently explored heterocyclic anti-inflammatory agents belonging to various classes such as pyrazole, pyrimidine, benzimidazole, indole, and other related heterocyclic compounds. In addition, an enlarged view on potential interactions of synthetic preparations with target inflammatory enzymes or cytokines has been provided. We have also enlisted lead compounds undergoing different clinical trials against inflammation. The elementary aim of this review is to provide restructured knowledge regarding heterocyclic molecules which will be valuable for the scientists working in the field of anti-inflammatory chemistry. The authors believe that lead compounds mentioned in the report will help to design and develop novel anti-inflammatory drug molecules targeting various factors involved in the progression of inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112438DOI Listing
August 2020

Medicinal Perspective of Indole Derivatives: Recent Developments and Structure-Activity Relationship Studies.

Curr Drug Targets 2020 ;21(9):864-891

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, G.T Road, Moga, Punjab, 142001, India.

Heterocyclic compounds play a significant role in various biological processes of the human body and many of them are in clinical use due to their diverse, chemical and biological properties. Among these, indole is one of the most promising pharmacologically active molecules. Due to its chemical reactivity, indole has been willingly modified to obtain a variety of new lead molecules, which has been successfully utilized to obtained novel drug candidates for the treatment of different pharmacological diseases. Indole-based compounds such as vincristine (anticancer), reserpine (antihypertensive), amedalin (antidepressant) and many more describe the medicinal and pharmacological importance of the indole in uplifting human life. In this review, we compiled various reports on indole derivatives and their biological significance, including antifungal, antiprotozoal, antiplatelet, anti- Alzheimer's, anti-Parkinson's, antioxidant and anticancer potential from 2015 onwards. In addition, structure-activity relationship studies of the different derivatives have been included. We have also discussed novel synthetic strategies developed during this period for the synthesis of different indole derivatives. We believe that this review article will provide comprehensive knowledge about the medicinal importance of indoles and will help in the design and synthesis of novel indole-based molecules with high potency and efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389450121666200310115327DOI Listing
January 2020

Recent advances in synthesis and medicinal chemistry of benzodiazepines.

Bioorg Chem 2020 04 17;97:103668. Epub 2020 Feb 17.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, G.T. Road, Ghal Kalan, Moga 142001, Punjab, India. Electronic address:

Benzodiazepines (BZDs) represent a diverse class of bicyclic heterocyclic molecules. In the last few years, benzodiazepines have emerged as potential therapeutic agents. As a result, several mild, efficient and high yielding protocols have been developed that offer access to various functionalized benzodiazepines (BZDs). They are known to possess a wide array of biological activities such as anxiolytic, anticancer, anticonvulsant, antipsychotics, muscle relaxant, anti-tuberculosis, and antimicrobial activities. The fascinating spectrum of biological activities exhibited by BZDs in various fields has prompted the medicinal chemist to design and discover novel benzodiazepine-based analogs as potential therapeutic candidates with the desired biological profile. In this review, an attempt has been made by to summarize (1) Recent advances in the synthetic chemistry of benzodiazepines which enable their synthesis with desired substitution pattern; (2) Medicinal chemistry of BZDs as therapeutic candidates with promising biological profile including insight of mechanistic studies; (3) The correlation of biological data with the structure i.e. structure-activity relationship studies were also included to provide an insight into the rational design of more active agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.103668DOI Listing
April 2020

Recent advances in the synthetic and medicinal perspective of quinolones: A review.

Bioorg Chem 2019 11 19;92:103291. Epub 2019 Sep 19.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, G.T. Road, Ghal Kalan, Moga 142001, Punjab, India. Electronic address:

In the modern scenario, the quinolone scaffold has emerged as a very potent motif considering its clinical significance. Quinolones possess wide range of pharmacological activities such as anticancer, antibacterial, antifungal, antiprotozoal, antiviral, anti-inflammatory, carbonic anhydrase inhibitory and diuretic activity etc. The versatile synthetic approaches have been successfully applied and several of the resulted synthesized compounds exhibit fascinating biological activities in numerous fields. This has prompted to discover quinolone-based analogues among the researchers due to its great diversity in biological activities. In the past few years, various new, efficient and convenient synthetic approaches (including green chemistry and microwave-assisted synthesis) have been designed and developed to synthesize diverse quinolone-based scaffolds which represent a growing area of interest in academic and industry as well as to explore their biological activities. In this review, an attempt has been made by the authors to summarize (1) One of the most comprehensive listings of quinolone-based drugs or agents in the market or under various stages of clinical development; (2) Recent advances in the synthetic strategies for quinolone derivatives as well as their biological implications including insight of mechanistic studies. (3) Further, the biological data is correlated with structure-activity relationship studies to provide an insight into the rational design of more active agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2019.103291DOI Listing
November 2019

Synthesis and biological evaluation of thiazolidine-2,4-dione-pyrazole conjugates as antidiabetic, anti-inflammatory and antioxidant agents.

Bioorg Chem 2019 11 10;92:103271. Epub 2019 Sep 10.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga 142001, Punjab, India. Electronic address:

A series of fourteen novel thiazolidine-2,4-dione derivatives clubbed with pyrazole moiety were synthesized via four step reaction procedure. Reactions were monitored by thin layer chromatography and were characterized by physicochemical and spectrophotometric (IR, Mass, HNMR and CNMR) analysis. The spectral data were in good agreement with their structures. The title compounds were docked against peroxisome proliferated activated receptors (PPAR-γ) and alpha-amylase and further evaluated for in vivo and in vitro antidiabetic, in vitro anti-inflammatory and antioxidant activities. Compound GB14 exhibited significant blood glucose lowering activity and was also found to be active inhibitor of alpha-amylase. Compound GB7 was found to be potent anti-inflammatory agent in terms of reducing inflammatory markers (TNF-α, IL-β, MDA) and also showed antioxidant activity to good extent. Therefore, these compounds may be considered as promising candidates for the development of new antidiabetic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2019.103271DOI Listing
November 2019

Corrigendum to"An insight into the medicinal perspective of synthetic analogs of indole: A review" [Eur. J. Med. Chem. 180 (2019) 562-612 11516].

Eur J Med Chem 2019 12 11;183:111680. Epub 2019 Sep 11.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.111680DOI Listing
December 2019

Design, synthesis, biological evaluation, and molecular modeling studies of rhodanine derivatives as pancreatic lipase inhibitors.

Arch Pharm (Weinheim) 2019 Oct 13;352(10):e1900029. Epub 2019 Aug 13.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Ghal Kalan, Moga, Punjab, India.

A series of rhodanine-3-acetic acid derivatives were synthesized via Knoevenagel condensation of rhodanine-3-acetic acid with various substituted aromatic aldehydes. The synthesized derivatives were screened in vitro for understanding the inhibitory potential towards pancreatic lipase (PL), a key enzyme responsible for the digestion of dietary fats. Derivative 8f exhibited a potential inhibitory activity towards PL (IC = 5.16 µM), comparable to that of the standard drug, orlistat (0.99 µM). An increase in the density of the aromatic ring resulted in potential PL inhibition. The enzyme kinetics of 8f exhibited a reversible competitive-type inhibition, similar to that of orlistat. Derivative 8f exhibited a MolDock score of -125.19 kcal/mol in docking studies, and the results were in accordance with their PL inhibitory potential. Furthermore, the reactive carbonyl group of 8f existed at a distance adjacent to Ser152 (≈3 Å) similar to that of orlistat. Molecular dynamics simulation (10 ns) of the 8f-PL complex revealed a stable binding conformation of 8f in the active site of PL (maximum root mean square displacement of ≈2.25 Å). The present study identified novel rhodanine-3-acetic acid derivatives with promising PL inhibitory potential, and further lead optimization might result in potent PL inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ardp.201900029DOI Listing
October 2019

An insight into the medicinal perspective of synthetic analogs of indole: A review.

Eur J Med Chem 2019 10 11;180:562-612. Epub 2019 Jul 11.

Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, Punjab, India.

Heterocycles occupy a salient place in chemistry due to their wide range of activity in the fields of drug design, photochemistry, agrochemicals, dyes, and so on. Amongst all, indole scaffold is considered as one of the most promising heterocycles found in natural and synthetic sources and has been shown to possess various biological activity, including anti-inflammatory, anti-HIV, antitubercular, antimalarial, anticonvulsant, antidiabetic, antihypertensive, analgesics, antidepressant, anticancer, antioxidant, antifungal, and antimicrobial, etc. All the reported indole molecules bind to multiple receptors with high affinity, thus expedite the research on the development of novel biologically active compounds through the various approach. In this review, we aimed to highlight synthetic and medicinal perspective on the development of indole-based analogs. In addition, structural activity relationship (SAR) study to correlate for their biological activity also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.07.019DOI Listing
October 2019

Neuroprotective effect of solanesol against 3-nitropropionic acid-induced Huntington's disease-like behavioral, biochemical, and cellular alterations: Restoration of coenzyme-Q10-mediated mitochondrial dysfunction.

Indian J Pharmacol 2018 Nov-Dec;50(6):309-319

Department of Pharmaceutical Sciences, PDM University, Bahadurgarh, Haryana, India.

Objective: The aim of the present study was to evaluate the solanesol (SNL)-mediated coenzyme-Q10 restoration to ameliorate 3-nitropropionic (3-NP)-induced behavioral, biochemical, and histological changes which resemble Huntington's disease (HD)-like symptoms in men.

Materials And Methods: Various behavioral and biochemical parameters were carried out to evaluate the activity of SNL on 3-NP-treated rats. To determine the therapeutic significance of SNL on HD, different behavioral tests such as memory task, locomotor activity, grip strength, and beam cross and some biochemical test along with histopathological findings were done.

Results: Chronic 3-NP, 10 mg/kg i.p., caused physical and mental abnormalities in animals, including memory impairment, weak grip strength, abnormal posture, and cognitive deficit. Biochemical analysis of brain homogenate in 3-NP-treated rats showed altered mitochondrial complexes, oxidative stress, and elevated lipid biomarkers. Neurohistological alterations of hippocampus, basal ganglia, and cerebral cortex of 3-NP-treated rats exhibit severe neuronal space, irregular damaged cells, and dense pyknotic nuclei-associated marked focal diffused gliosis. SNL administered for 15 days significantly improved motor performance and cognitive behavior task and restored the histopathological changes. Further, SNL treatment significantly improved mitochondrial complexes such as coenzyme-Q10 enzyme activity and attenuated inflammatory and oxidative damage of rat brain.

Conclusion: In the present research work, SNL (5, 10, and 15 mg/kg p.o.) provided notable neuroprotective effect, which was confirmed by behavioral paradigms and biochemical test. It restored the behavioral and biochemical alteration caused by 3-NP and confirmed the strong neuroprotective mechanism of SNL in 3-NP-intoxicated memory and cognitive abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijp.IJP_11_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364342PMC
June 2019

Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors.

Bioorg Med Chem Lett 2017 08 28;27(16):3749-3754. Epub 2017 Jun 28.

Laboratory of Natural Drugs, Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani Campus, Pilani 333 031, Rajasthan, India. Electronic address:

A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz., methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively. Compound 11e exhibited potent PL inhibitory activity (IC=4.81µM and X=10.01, respectively in method A and B), comparable to that of the standard drug, orlistat (IC=0.99µM and X=3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking studies validated the rationale of pharmacophoric design and are in accordance to the in vitro results. Compound 11e exhibited a potential MolDock score of -153.349kcal/mol. Further, the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the hydrophobic lid domain. Moreover, the carbonyl group at 2 position of the TZD ring existed adjacent to Ser 152 (≈3Å) similar to that of orlistat. A 10ns molecular dynamics simulation of 11e-PL complex revealed a stable binding conformation of 11e in the active site of PL (Maximum RMSD≈3Å). The present study identified novel thiazolidinedione based leads with promising PL inhibitory activity. Further development of the leads might result in potent PL inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2017.06.069DOI Listing
August 2017

p53-Mdm2 Interaction Inhibitors as Novel Nongenotoxic Anticancer Agents.

Curr Cancer Drug Targets 2018 ;18(8):749-772

Department of Chemistry, Sant Longowal Institute of Engineering & Technology (Deemed University), Longowal, Sangrur-148106, India.

Background: Cancer is a major global health problem with high mortality rate. Most of the clinically used anticancer agents induce apoptosis through genotoxic stress at various stages of cell cycle and activation of p53. Acting as a tumor suppressor, p53 plays a vital role in preventing tumor development. Tumor suppressor function of p53 is effectively antagonized by its direct interaction with murine double minute 2 (Mdm2) proteins via multiple mechanisms. Thus, p53-Mdm2 interaction has been found to be an important target for the development of novel anticancer agents. Currently, nutlin, spirooxindole, isoquilinone and piperidinone analogues inhibiting p53-Mdm2 interaction are found to be promising in the treatment of cancer.

Objective: The current review focused to scrutinize the structural aspects of p53-Mdm2 interaction inhibitors.

Methods: The present study provides a detailed collection of published information on different classes of inhibitors of p53-Mdm2 interaction as potential anticancer agents. The review highlighted the structural aspects of various reported p53-Mdm2 inhibitors for optimization.

Results: In the last few years, different classes of inhibitors of p53-Mdm2 have been designed and developed, and seven such compounds are being evaluated in clinical trials as new anticancer drugs. Further, to explore the role of p53 protein as a potential target for anticancer drug development, in this review, the mechanism of Mdm2 mediated inactivation of p53 and recent developments on p53- Mdm2 interactions inhibitors are discussed.

Conclusion: Agents designed to block the p53-Mdm2 interaction may have a therapeutic potential for the treatment of a subset of human cancers retaining wild-type p53. We review herein the recent advances in the design and development of potent small molecules as p53-Mdm2 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568009617666170623111953DOI Listing
October 2019

Synthesis, characterization of (Z)-N-(1-(2-(2-amino-3-(dimethylamino) methyl)phenyl)-5-phenyl-1,3,4, oxadiazol-3(2H)-yl)ethanone analogs as potent antimicrobial and hydrogen peroxide scavenging agents.

Med Chem 2013 Aug;9(5):710-7

Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, India.

A series of (Z)-N-(1-(2-(2-amino-3-((dimethylamino) methyl) phenyl)-5-phenyl-1,3,4,oxadiazol-3(2H)- yl)ethanone derivatives was prepared and studied for its antimicrobial and antioxidant activities. Among the synthesized derivatives, compounds (7c) (Z)-N-(1-(2-(2-amino-3-((dimethylamino)methyl)phenyl)-5-phenyl-1,3,4-oxadiazol-3(2H)- yl)ethylidene)-4-chloroaniline, (7g) (Z)-N-(1-(2-(2-amino-3-((dimethylamino)methyl)phenyl)-5-phenyl-1,3,4-oxadiazol- 3(2H)-yl)ethylidene)-4-nitroaniline and (7i) (Z)-N-(1-(2-(2-amino-3-((dimethylamino)methyl)phenyl)-5-phenyl-1,3,4- oxadiazol-3(2H)-yl)ethylidene)-4-methoxyaniline were found to be the most effective antimicrobial compounds. While the compounds 7c and 7g were the most potent antioxidant compounds with significant hydrogen peroxide scavenging activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1573406411309050011DOI Listing
August 2013

Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin-releasing hormone (TRH) analogues.

ChemMedChem 2011 Mar 7;6(3):531-43. Epub 2011 Feb 7.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.

As part of our search for selective and CNS-active thyrotropin-releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH-R1 and TRH-R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH-R1 and TRH-R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R=CH3) exhibited binding affinities (Ki values) of 0.17 μM for TRH-R1 and 0.016 μM for TRH-R2; it is 10-fold less potent than TRH in binding to TRH-R1 and equipotent with TRH in binding to TRH-R2. Compound 21 a, the most selective agonist, activated TRH-R2 with a potency (EC50 value) of 0.0021 μM, but activated TRH-R1 at EC50=0.05 μM, and exhibited 24-fold selectivity for TRH-R2 over TRH-R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate-induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a,b and 22 a,b decreased sleeping time by nearly 50% more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ-induced seizures, but failed to provide any protection in MES-induced seizures at 10 μmol kg(-1). The results of this study provide evidence that TRH analogues that show selectivity for TRH-R2 over TRH-R1 possess potent CNS activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201000481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479646PMC
March 2011

Neuropharmacological profile of L-pGlu-(1-benzyl)-L-His-L-ProNH2, a newer thyrotropin-releasing hormone analog: effects on seizure models, sodium current, cerebral blood flow and behavioral parameters.

Epilepsy Res 2009 Dec 14;87(2-3):223-33. Epub 2009 Oct 14.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India.

In the present study, L-pGlu-(1-benzyl)-L-His-L-ProNH(2) (NP-355), a newer CNS active thyrotropin-releasing hormone (TRH) analog was evaluated for its antiepileptic potential. NP-355 (5, 10 and 20 micromol/kg; i.v.) pretreatment significantly delayed onset and reduced the frequency of convulsions in pentylenetetrazole-induced seizures. NP-355 was also found to be protective against picrotoxin- and kainic acid-induced seizures. Maximum electroshock-induced seizures were not protected even at 20 micromol/kg in mice. Effects of NP-355 on functional observation battery did not exhibit any undesirable effects. Moreover, the antiepileptic activity produced by NP-355 was observed without significantly altering mean arterial blood pressure. NP-355 significantly increases the CBF to 17+/-3% as compared to saline (6+/-2%). NP-355 (100, 300 and 1000 microM) produces a concentration-dependent depression (16%, 63% and 77%, respectively) of the peak sodium current. NP-355 did not alter neurobehavioral parameters. This study demonstrates that NP-355 has potential antiepileptic activity and devoid of undesirable effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2009.09.007DOI Listing
December 2009

Chemistry and biology of thyrotropin-releasing hormone (TRH) and its analogs.

Curr Med Chem 2008 ;15(26):2718-33

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab 160 062, India.

Thyrotropin-releasing hormone (TRH), a hypothalamic orally active neuropeptide, has been manifested in a wide range of biological responses. Besides its central role in regulating the pituitary-thyroid axis by simulating the release of thyrotropin, TRH has considerable influence on the activity of a number of neurobiological systems. Due to the therapeutic potential of TRH to treat several CNS maladies, the development of CNS-selective and metabolically stable TRH analogs is an area of interest. TRH is known to elicit its biological response through two G-protein coupled receptors for TRH (namely, TRH-R1 and TRH-R2). The distinct distribution of TRH receptors in tissues has provided opportunity to discover receptor subtype-specific analogs, which would demonstrate high CNS activities, and are completely free of hormonal activities. In this review, an in-depth analysis of the chemistry and biology of TRH and its analogs is provided. Recent discoveries of TRH-R2 selective analogs, TRH super agonists, metabolically stable TRH analogs, and targeted delivery of TRH analogs have been also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/092986708786242912DOI Listing
March 2009

Antiepileptic potential and behavioral profile of L-pGlu-(2-propyl)-L-His-L-ProNH2, a newer thyrotropin-releasing hormone analog.

Epilepsy Behav 2009 Jan 13;14(1):48-53. Epub 2008 Nov 13.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India.

Thyrotropin-releasing hormone (TRH) and its analogs have a number of neurobiological functions and therapeutic uses in disorders of the central nervous system. In this study, the newly synthesized TRH analogs were evaluated for central nervous system activity in pentobarbital-induced sleeping in mice. The most potent TRH analog (L-pGlu-(2-propyl)-L-His-L-ProNH(2) coded as NP-647) was evaluated for its antiepileptic potential in various seizure models in mice in comparison with TRH. Intravenous pretreatment with NP-647 (10 and 20 micromol/kg body wt) significantly delayed the onset and reduced the frequency of convulsions in the pentylenetetrazole model, but not in the maximum electroshock seizure model. Also, it was found to be protective against picrotoxin- and kainic acid-induced seizures. However, NP-647 did not significantly affect theophylline-induced seizures. Further study of the effect of NP-647 on locomotor activity and a functional observational battery revealed that it did not significantly exhibit any undesirable effects as compared with vehicle and TRH. NP-647 did not significantly affect cerebral blood flow, whereas the native peptide TRH markedly increased cerebral blood flow. Furthermore, NP-647 exerted antiepileptic activity without significantly altering plasma thyroid-stimulating hormone levels and mean arterial blood pressure. This suggests that NP-647 is more selective for central nervous system activity and devoid of hormonal and cerebrovascular system effects. In contrast, TRH exhibited cardiac and endocrine effects as marked by significant elevation in mean arterial blood pressure and plasma thyroid-stimulating hormone levels. This study demonstrates that NP-647 has potential antiepileptic activity devoid of undesirable effects and, thus, can be exploited for the prevention and treatment of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2008.10.006DOI Listing
January 2009

Selectivity-based QSAR approach for screening and evaluation of TRH analogs for TRH-R1 and TRH-R2 receptors subtypes.

J Mol Graph Model 2008 Oct 27;27(3):309-20. Epub 2008 May 27.

Centre of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160062, Punjab, India.

Design and development of therapeutically useful CNS selective thyrotropin-releasing hormone (TRH) analogs acting on TRH-R2 receptor subtype, exerting weak or no TRH-R1-mediated TSH-releasing side effects has gained imagination of researchers in the recent past. The present study reports the development and implementation of a selectivity-based QSAR approach for screening selective agonists of TRH-R2 receptor subtype. The statistically significant predictive models were thoroughly validated using an external validation set whose activity was previously unknown. The model was able to predict preference for either of the receptor subtypes successfully.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmgm.2008.05.005DOI Listing
October 2008

Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines.

Bioorg Med Chem 2007 Jan 1;15(2):626-40. Epub 2006 Nov 1.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.

Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC=6.25 microg/mL, 99% inhibition, Mycobacterium tuberculosis H37Rv) has led to two series of 4-(adamantan-1-yl)-2-substituted quinolines (Series 1-2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid N'-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs 7, 9, 20, and 21 displayed MIC of 3.125 microg/mL. Further investigation of AQCH by its reaction with various aliphatic, aromatic, and heteroaromatic aldehydes led to the synthesis of 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidene hydrazides (Series 2). Analogs 42-44 and 48 have produced promising antimycobacterial activities (99% inhibition) at 3.125 microg/mL against drug-sensitive M. tuberculosis H37Rv strain. The most potent analog 35 of the series produced 99% inhibition at 1.00 microg/mL against drug-sensitive strain, and MIC of 3.125 microg/mL against isoniazid-resistant TB strain. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by three methods-comparative molecular field analysis (CoMFA), CoMFA with inclusion of a hydropathy field (HINT), and comparative molecular similarity indices analysis (CoMSIA). Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a test set of molecules was the best for the CoMFA model generated with database alignment. Based on the CoMFA contours, we have tried to explain the structure-activity relationships of the compounds reported herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2006.10.064DOI Listing
January 2007

Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1.

Bioorg Med Chem 2007 Jan 10;15(1):433-43. Epub 2006 Oct 10.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.

Thyrotropin-releasing hormone (TRH) analogs in which the N-1(tau) or the C-2 position of the imidazole ring of the histidine residue is substituted with various alkyl groups and the l-pyroglutamic acid (pGlu) is replaced with the l-pyro-2-aminoadipic acid (pAad) or (R)- and (S)-3-oxocyclopentane-1-carboxylic acid (Ocp) were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). We observed that several analogs were selective agonists of TRH-R2 showing relatively less or no activation of TRH-R1. For example, the most selective agonist of the series 13, in which pGlu is replaced with the pAad and histidine residue is substituted at the N-1 position with an isopropyl group, was found to activate TRH-R2 with a potency (EC(50)=1.9microM) but did not activate TRH-R1 (potency>100 microM); that is, exhibited >51-fold greater selectivity for TRH-R2 versus TRH-R1. Analog 8, in which pGlu is replaced with pAad and histidine is substituted at the N-1(tau) position with a methyl group, exhibited a binding affinity (K(i)=0.0032 microM) to TRH-R1 that is similar to that of [Ntau(1)-Me-His]-TRH and displayed potent activation of TRH-R1 and TRH-R2 (EC(50)=0.0049 and 0.0024 microM, respectively). None of the analogs in which pGlu is replaced with the bioisosteric (R)- and (S)-(Ocp) and the imidazole ring is substituted at the N-1(tau) or C-2 position were found to bind or activate either TRH-R1 or TRH-R2 at the highest test dose of 100 microM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2006.09.045DOI Listing
January 2007

Synthesis, receptor binding, and activation studies of N(1)-alkyl-L-histidine containing thyrotropin-releasing hormone (TRH) analogues.

Bioorg Med Chem 2006 Sep 2;14(17):5981-8. Epub 2006 Jun 2.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.

Thyrotropin-releasing hormone (TRH) analogues in which the N(1)-position of the imidazole ring of the centrally placed histidine residue is substituted with various alkyl groups were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). Analogue 3 (R=C2H5) exhibited binding affinity (Ki) of 0.012 microM to TRH-R1 that is about 1.1-fold higher than that of TRH. Several analogues were found to selectively activate TRH-R2 with greater potency than TRH-R1. The most selective agonist of the series 5 [R=CH(CH3)2] was found to activate TRH-R2 with a potency (EC50) of 0.018 microM but could only activate TRH-R1 at EC50 value of 1.6 microM; that is, exhibited 88-fold greater potency for TRH-R2 versus TRH-R1. The results of this study indicate that modulation of central histidine residue is important for designing analogues which were selective agonist at TRH receptor subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2006.05.031DOI Listing
September 2006

Low affinity analogs of thyrotropin-releasing hormone are super-agonists.

J Biol Chem 2006 May 21;281(19):13103-13109. Epub 2006 Mar 21.

Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892. Electronic address:

We show that several analogs of thyrotropin-releasing hormone (TRH) are more efficacious agonists at TRH receptors R1 and R2 than TRH itself. The apparent efficacies of the analogs were inversely related to their potencies and were independent of the nature of the modifications in TRH structure. In studies in intact cells, we showed that the differences in apparent efficacies were not due to differences in G-protein coupling, receptor desensitization, or recycling. Moreover, the differences in efficacies persisted in experiments using accessory protein-free membranes. We conclude that the efficacy differences of TRH analogs originated from the enhanced ability of TRH-R complexed to the low affinity agonists to directly activate G-protein(s), and not by a modulation of the activity of accessory proteins, and propose possible mechanisms for this phenomenon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M600440200DOI Listing
May 2006

Ring-substituted quinolines. Part 2: Synthesis and antimycobacterial activities of ring-substituted quinolinecarbohydrazide and ring-substituted quinolinecarboxamide analogues.

Bioorg Med Chem 2004 Dec;12(24):6465-72

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India.

Additional structural modifications of the new chemical entity, 2,8-dicyclopentyl-4-methylquinoline (DCMQ; MIC=6.25 microg/mL, M. tuberculosis H37Rv) resulted in the synthesis of four new series of the ring-substituted quinolinecarbohydrazides (series 1-4) constituting 22 analogues. All new derivatives were evaluated for in vitro antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Certain ring-substituted-2-quinolinecarbohydrazide analogues described herein showed good inhibitory activity. In particular, analogues 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d), 4,5-dicyclopentyl-2-quinolinecarbohydrazide (2e), 4,8-dicyclopentyl-2-quinolinecarbohydrazide (2f), and 4,5-dicyclohexyl-2-quinolinecarbohydrazide (2g) have exhibited the MIC value of 6.25 microg/mL. Further investigation of the most suitable lead prototype, 4-(1-adamantyl)-2-quinolinecarbohydrazide (2d, series 1) led to the synthesis of N2-alkyl/N2,N2-dialkyl/N2-aryl-4-(1-adamantyl)-2-quinolinecarboxamides (series 5) consisting of 13 analogues. Some of the synthesized carboxamides 7a, 7h, and 7m reported herein have exhibited excellent antimycobacterial activities in the range of 6.25-3.125 microg/mL against drug-sensitive and drug-resistant M. tuberculosis H37Rv strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2004.09.017DOI Listing
December 2004

Synthesis and antimycobacterial activities of ring-substituted quinolinecarboxylic acid/ester analogues. Part 1.

Bioorg Med Chem 2004 Aug;12(15):4179-88

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, Punjab 160 062, India.

Structural optimization of recently discovered new chemical entity, 2,8-dicyclopentyl-4-methylquinoline (DCMQ; MIC= 6.25 microg/mL, M. tuberculosis H37Rv) resulted in the synthesis of four new series of ring-substituted quinolinecarboxylic acids/esters constituting 45 analogues. All new derivatives were evaluated for in vitro antimycobacterial activities against M. tuberculosis H37Rv. Certain ring-substituted-2-quinolinecarboxylic acid ester and ring-substituted-2-quinoline acetic acid ester analogues described herein showed moderate to good inhibitory activity. In particular, three analogues methyl 4,5-dicyclopentyl-2-quinolinecarboxylate (3b), methyl 4,8-dicyclopentyl-2-quinolinecarboxylate (3c) and ethyl 2-(2,8-dicyclopentyl-4-quinolyl)acetate (14g) exhibited excellent MIC values of 1.00, 2.00 and 4.00microg/mL, respectively. Results obtained indicate that substitution of the quinoline ring with dicyclopentyl substituent presumably enhances the antimycobacterial activities in the quinoline analogues described herein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2004.05.018DOI Listing
August 2004