Publications by authors named "Vipan Kumar"

83 Publications

1H-1,2,3-triazole grafted tacrine-chalcone conjugates as potential cholinesterase inhibitors with the evaluation of their behavioral tests and oxidative stress in mice brain cells.

Bioorg Chem 2021 Jun 6;114:105053. Epub 2021 Jun 6.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

The present paper explicates the synthesis of 1H-1,2,3-triazole tethered tacrine-chalcone conjugates and evaluation of their AChE and BuChE inhibitory activity. In-vitroAChE inhibition assay revealed three compounds, 9h, 9i, and 11f, being more potent than the standard drug tacrine and further evaluated against butyrylcholinesterase. The present study was extended to investigate the anti-amnestic effect of promising compoundson scopolamine-induced behavioral and neurochemical changes in mice. Inclined plane model and Elevated plus-maze model were performed to assess general limb motor activity and anxiety-like behavior, respectively, in mice pre-treated with scopolamine. Oxidative stress parameters reduced glutathione contents (GSH) and lipid peroxidation products (TBARS) in the brain homogenates as estimated using ex-vivo studies. Furthermore, molecular docking studies were performed for the potent compounds to decipher the mechanism of observed activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2021.105053DOI Listing
June 2021

Biological and Biochemical Evaluation of Isatin-Isoniazid Hybrids as Bactericidal Candidates against .

Antimicrob Agents Chemother 2021 Jul 16;65(8):e0001121. Epub 2021 Jul 16.

Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, Montpellier, France.

Tuberculosis remains a leading cause of mortality among infectious diseases worldwide, prompting the need to discover new drugs to fight this disease. We report here the design, synthesis, and antimycobacterial activity of isatin-mono/bis-isoniazid hybrids. Most of the compounds exhibited very high activity against Mycobacterium tuberculosis, with MICs in the range of 0.195 to 0.39 μg/ml, and exerted a more potent bactericidal effect than the standard antitubercular drug isoniazid (INH). Importantly, these compounds were found to be well tolerated at high doses (>200 μg/ml) on Vero kidney cells, leading to high selectivity indices. Two of the most promising hybrids were evaluated for activity in THP-1 macrophages infected with M. tuberculosis, among which compound 11e was found to be slightly more effective than INH. Overexpression of InhA along with cross-resistance determination of the most potent compounds, selection of resistant mutants, and biochemical analysis, allowed us to decipher their mode of action. These compounds effectively inhibited mycolic acid biosynthesis and required KatG to exert their biological effects. Collectively, this suggests that the synthesized isatin-INH hybrids are promising antitubercular molecules for further evaluation in preclinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00011-21DOI Listing
July 2021

A trio of quinoline-isoniazid-phthalimide with promising antiplasmodial potential: Synthesis, in-vitro evaluation and heme-polymerization inhibition studies.

Bioorg Med Chem 2021 Jun 18;39:116159. Epub 2021 Apr 18.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

Quinoline-isoniazid-phthalimide triads have been synthesised to assess their antiplasmodial efficacy and cytotoxicity against chloroquine-resistant W2 strain of P. falciparum and Vero cells, respectively. Most of the synthesized compounds displayed IC in lower nM range and appeared to be approximately five to twelve fold more active than chloroquine. Heme-binding studies were also carried out to delineate the mode of action. The promising compounds with IC in range of 11-30 nM and selectivity index >2800, may act as promising template for the design of new antiplasmodials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2021.116159DOI Listing
June 2021

Rupture of portal vein pseudoaneurysm caused by impinging infected walled off pancreatic necrosis (WOPN): a rare complication.

BMJ Case Rep 2021 Mar 10;14(3). Epub 2021 Mar 10.

Department of Surgical Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

We report a case of walled off pancreatic necrosis in a patient with alcoholic pancreatitis who underwent endoscopic ultrasound-guided multiple pigtail catheter drainage. 10 days later patient presented with massive haemorrhage likely due to erosion of portal vein pseudoaneurysm caused by decubitus of pigtails. Patient required emergent portal venorrhaphy to arrest haemorrhage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2020-239045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949384PMC
March 2021

Synthesis and antiplasmodial evaluation of 1H-1,2,3-triazole grafted 4-aminoquinoline-benzoxaborole hybrids and benzoxaborole analogues.

Bioorg Chem 2021 Apr 16;109:104733. Epub 2021 Feb 16.

Department of Chemistry, Guru Nanak Dev University, Amritsar, India. Electronic address:

A library of 1H-1,2,3-triazole-tethered 4-aminoquinoline-benzoxaborole hybrids as well as aryl substituted benzoxaborole analogues was synthesized and screened for their anti-plasmodial efficacy against both chloroquine-susceptibility 3D7 and chloroquine-resistant W2 strains of P. falciparum. The inclusion of quinoline core among the synthesized analogues resulted in substantial enhancement of anti-plasmodial activities. Further, the spacer of a flexible alkyl chain is marginally preferred over piperazyl-ethyl in inhibiting growth of P. falciparum. The most potent 4-aminoquinoline-benzoxaborole conjugate with ethyl as spacer exhibited IC values of 4.15 and 3.78 μM against 3D7 CQ-susceptible and W2 CQ-resistant strains of P. falciparum with lower cross resistance with Chloroquine. There was no difference in anti-plasmodial activities between the CQ-susceptible 3D7 and CQ-resistant W2 strains of P. falciparum for the benzoxaborole derivatives lacking a quinoline core.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2021.104733DOI Listing
April 2021

Recent accomplishments on the synthetic/biological facets of pharmacologically active 1H-1,2,3-triazoles.

Eur J Med Chem 2021 Feb 3;212:113069. Epub 2020 Dec 3.

Department of Chemistry, Guru Nanak Dev University, Amritsar, 143005, Punjab, India. Electronic address:

The continuous demand of medicinally important scaffolds has prompted the synthetic chemists to identify simple and efficient routes for their synthesis. 1H-1,2,3-triazole, obtained by highly versatile, efficacious and selective "Click Reaction" has become a synthetic/medicinal chemist's favorite not only because of its ability to mimic different functional groups but also due to enhancement in the targeted biological activities. Triazole ring has also been shown to play a critical role in biomolecular mimetics, fragment-based drug design, and bioorthogonal methodologies. In addition, the availability of triazole containing drugs such as fluconazole, furacyclin, etizolam, voriconazole, triozolam etc. in market has underscored the potential of this biologically enriched core in expediting development of new scaffolds. The present review, therefore, is an attempt to highlight the recent synthetic/biological advancements in triazole derivatives that could facilitate the in-depth understanding of its role in the drug discovery process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.113069DOI Listing
February 2021

Amide Tethered 4-Aminoquinoline-naphthalimide Hybrids: A New Class of Possible Dual Function Antiplasmodials.

ACS Med Chem Lett 2020 Dec 23;11(12):2544-2552. Epub 2020 Nov 23.

Department of Chemistry, Guru Nanak Dev University, Amritsar, Pin 143005, India.

A series of amide tethered 4-aminoquinoline-naphthalimide hybrids has been synthesized to assess their in vitro antiplasmodial potential against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of . The most active and noncytotoxic compound had an IC value of 0.07 μM against W2 strain and was more active than standard antimalarial drugs, including chloroquine, desethylamodiaquine, and quinine, particularly for drug resistant malaria. The promising scaffold, when subjected to heme binding and molecular modeling studies, was identified as a possible potent inhibitor of hemozoin formation and chloroquine resistance transporter (PfCRT), respectively, and, therefore, could act as a dual function antiplasmodial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734791PMC
December 2020

Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?

Expert Opin Drug Discov 2021 Apr 30;16(4):335-363. Epub 2020 Dec 30.

Department of Chemistry, Guru Nanak Dev University, Amritsar-India.

Introduction: Cancer continues to be a big threat and its treatment is a huge challenge among the medical fraternity. Conventional anti-cancer agents are losing their efficiency which highlights the need to introduce new anti-cancer entities for treating this complex disease. A hybrid molecule has a tendency to act through varied modes of action on multiple targets at a given time. Thus, there is the significant scope with hybrid compounds to tackle the existing limitations of cancer chemotherapy.

Area Covered: This perspective describes the most significant hybrids that spring hope in the field of cancer chemotherapy. Several hybrids with anti-proliferative/anti-tumor properties currently approved or in clinical development are outlined, along with a description of their mechanism of action and identified drug targets.

Expert Opinion: The success of molecular hybridization in cancer chemotherapy is quite evident by the number of molecules entering into clinical trials and/or have entered the drug market over the past decade. Indeed, the recent advancements and co-ordinations in the interface between chemistry, biology, and pharmacology will help further the advancement of hybrid chemotherapeutics in the future.: Deoxyribonucleic acid, DNA; national cancer institute, NCI; peripheral blood mononuclear cells, PBMC; food and drug administration, FDA; histone deacetylase, HDAC; epidermal growth factor receptor, EGFR; vascular endothelial growth factor receptor, VEGFR; suberoylanilide hydroxamic acid, SAHA; farnesyltransferase inhibitor, FTI; adenosine triphosphate, ATP; Tamoxifen, TAM; selective estrogen receptor modulator, SERM; structure activity relationship, SAR; estrogen receptor, ER; lethal dose, LD; half maximal growth inhibitory concentration, GI; half maximal inhibitory concentration, IC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17460441.2021.1850686DOI Listing
April 2021

Design, Synthesis, Antiproliferative Evaluation, and Molecular Docking Studies of -(3-Hydroxyindole)-Appended β-Carbolines/Tetrahydro-β-Carbolines Targeting Triple-Negative and Non-Triple-Negative Breast Cancer.

ACS Omega 2020 Nov 5;5(45):28907-28917. Epub 2020 Nov 5.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.

The present manuscript pertains to the design and synthesis of a series of 3-hydroxyindole-substituted β-carbolines/tetrahydro-β-carbolines with an aim to explore their antiproliferative structure-activity relationship against breast cancer. The conjugate with an optimum combination of a flexible tetrahydro-β-carboline core, a tertiary alcoholic group along with a chloro substituent on the indole ring, proved to be the most active compound. It displayed IC values of 13.61 and 22.76 μM against MCF-7 (ER+) and MDA-MB-231 (ER-) cells, respectively. The docking studies were found to be consistent with experimental results owing to the stronger binding affinity of the synthesized conjugates via hydrophobic and H-bonding interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.0c01226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675558PMC
November 2020

Design and synthesis of 4-Aminoquinoline-isoindoline-dione-isoniazid triads as potential anti-mycobacterials.

Bioorg Med Chem Lett 2020 11 24;30(22):127576. Epub 2020 Sep 24.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

A series of 4-aminoquinoline-isoindoline-dione-isoniazid triads were synthesized and assessed for their anti-mycobacterial activities and cytotoxicity. Most of the synthesized compounds exhibited promising activities against the mc6230 strain of M. tuberculosis with MIC in the range of 5.1-11.9 µM and were non-cytotoxic against Vero cells. The conjugates lacking either isoniazid or quinoline core in their structural framework failed to inhibit the growth of M. tuberculosis; thus, further strengthening the proposed design of triads in the present study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127576DOI Listing
November 2020

Diacetoxy iodobenzene mediated regioselective synthesis and characterization of novel [1,2,4]triazolo[4,3-a]pyrimidines: apoptosis inducer, antiproliferative activities and molecular docking studies.

J Biomol Struct Dyn 2021 Aug 18;39(12):4398-4414. Epub 2020 Jun 18.

Department of Chemistry, National Institute of Technology (NIT), Kurukshetra, Haryana, India.

Prompt and regioselective synthesis of eleven novel [1,2,4]triazolo[4,3-a]pyrimidines , intramolecular oxidative-cyclization of 2-(2-arylidenehydrazinyl)-4-methyl-6-phenylpyrimidine derivatives has been demonstrated here using diacetoxy iodobenzene (DIB) as inexpensive and ecofriendly hypervalent iodine(III) reagent in CHCl at room temperature. Regiochemistry of final product has been established by developing single crystal and studied X-ray crystallographic data for two derivatives and without any ambiguity. These prominent [1,2,4]triazolo[4,3-a]pyrimidines were evaluated for human osteosarcoma bone cancer (MG-63) and breast cancer (MCF-7) cell lines using MTT assay to find potent antiproliferative agent and also on testicular germ cells to find potent apoptotic inducing activities. All compounds show significant cytotoxicity, particularly 3-(2,4-dichlorophenyl)-5-methyl-7-phenyl-[1,2,4]triazolo[4,3-a]pyrimidine () was found significant apoptotic inducing molecule, as well as the most potent cytotoxic agent against bone cancer (MG-63) and breast cancer (MCF-7) cell lines with GI value 148.96 µM and 114.3 µM respectively. Molecular docking studies has been carried out to see the molecular interactions of synthesized compounds with the protein thymidylate synthase (PBD ID: 2G8D).Communicated by Ramaswamy H. Sarma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2020.1777900DOI Listing
August 2021

Amalgamating Isatin/Indole/Nitroimidazole with 7-chloroquinolines via azide-alkyne cycloaddition: Synthesis, anti-plasmodial, and cytotoxic evaluation.

Chem Biol Drug Des 2020 12 25;96(6):1355-1361. Epub 2020 Jun 25.

Department of Chemistry, Guru Nanak Dev University, Amritsar, India.

The present paper describes the synthesis, anti-plasmodial, and cytotoxic evaluation of 7-chloroquinoline-based conjugates with isatins/indoles/ nitroimidazoles, obtained via Cu-promoted 1,3-dipolar cycloadditions. On contemplating SAR of the synthesized series, the inclusion of indole and nitroimidazole-core improved the anti-plasmodial activities while the isatin seemed to have a lesser effect. The conjugate with a nitroimidazole-core and hexyl chain length as a spacer between the two pharmacophores was found to be most potent among the synthesized series and displayed an IC of 0.12 µM and a selectivity index of 1748.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cbdd.13738DOI Listing
December 2020

Functionalized Naphthalimide-4-aminoquinoline Conjugates as Promising Antiplasmodials, with Mechanistic Insights.

ACS Med Chem Lett 2020 Feb 8;11(2):154-161. Epub 2020 Jan 8.

Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab, India.

A series of 25 conjugates has been synthesized to evaluate their antiplasmodial potency and cytotoxicity against the chloroquine resistant (CQR) W2 strain of and Vero kidney cell lines, respectively. Most of the compounds showed IC values in the lower nM range and proved to be many fold more active than chloroquine (CQ). The studies were extended to decipher modes of action using techniques including UV-vis absorption, NMR titrations, and mass spectrometry, and conclusions were strengthened by docking and density functional theory (DFT) simulations. The most active compound, with IC 15 nM and selectivity index >4000, proved to be an interesting template for antimalarial drug discovery. To the best of our knowledge this is the first report of a potent naphthalimide based antiplasmodial conjugate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.9b00521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025377PMC
February 2020

Design, synthesis, heme binding and density functional theory studies of isoindoline-dione-4-aminoquinolines as potential antiplasmodials.

Future Med Chem 2020 02 5;12(3):193-205. Epub 2019 Dec 5.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India.

WHO Malaria report 2017 estimated 216 million cases of malaria and 445,000 deaths worldwide, with 91% of deaths affecting the African region. Microwave promoted the synthesis of cycloalkyl amine substituted isoindoline-1,3-dione-4-aminoquinolines was urbanized for evaluating their antiplasmodial activities. Compound with the optimum combination of propyl chain length and hydroxyethyl piperazine proved to be the most potent among the synthesized scaffolds against chloroquine-resistant W2 strain of with an IC value of 0.006 μM. Heme-binding along with density functional theory studies were further carried out in order to delineate the mechanism of action of the most active compound. The synthesized scaffold can act as a therapeutic template for further synthetic modifications toward the search for a new antimalarial agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/fmc-2019-0260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099627PMC
February 2020

Synthesis, anti-plasmodial and cytotoxic evaluation of 1H-1,2,3-triazole/acyl hydrazide integrated tetrahydro-β-carboline-4-aminoquinoline conjugates.

Bioorg Med Chem Lett 2020 01 11;30(2):126810. Epub 2019 Nov 11.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

A series of 1H-1,2,3-triazole/acylhydrazide-tethered tetrahydro-β-carboline-4-aminoquinoline conjugates was synthesized with an aim to study their anti-plasmodial structure-activity relationship. The presence of 1H-1,2,3-triazole-core along with a flexible alkyl chain length on aminoquinoline core has favourable influence on the anti-plasmodial activity against Chloroquine-resistant W2 strain of P. falciparum while the introduction of hydrazine core not only diminished the activities but also resulted in increased cytotoxicity against mammalian Vero cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2019.126810DOI Listing
January 2020

Variedly connected 1,8-naphthalimide-7-chloroquinoline conjugates: Synthesis, anti-mycobacterial and cytotoxic evaluation.

Bioorg Chem 2019 11 4;92:103241. Epub 2019 Sep 4.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

Recent disclosures about anti-bacterial and anti-tubercular potential of naphthalimide and quinoline core respectively propelled us to synthesize a library of 1,8-naphthalimide-7-chloroquinoline hybrids. Different modes of linkage between two pharmacophoric units viz. simple alkyl chains and induction of amide bond were used and the substituents on the naphthalimide core were varied in order to determine Structure-Activity-Relationship (SAR). Our findings demonstrated that simple alkyl chain linked conjugates showed better activity profiles without any cytotoxicity, while the inclusion of amide bond enhanced the cytotoxic tendency. An interesting behaviour of conjugates in terms of activity and cytotoxicity was observed via switching over the nature of linker between two pharmacophores.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2019.103241DOI Listing
November 2019

Substituted 1,3-dioxoisoindoline-4-aminoquinolines coupled via amide linkers: Synthesis, antiplasmodial and cytotoxic evaluation.

Bioorg Chem 2019 07 11;88:102912. Epub 2019 Apr 11.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

Synthesis of C-5-substituted 1,3-dioxoisoindoline-4-aminoquinolines having amide group as a spacer was developed with an intent to evaluate their antiplasmodial activities. The synthesized dioxoisoindoline-aminoquinolines tethered with β-alanine as a spacer and secondary amine as substituent displayed good anti-plasmodial activities. Compound 7j, with an optimum combination of β-alanine and an ethyl chain length as linker along with diethylamine as the secondary amine counterpart at dioxoisoindoline proved to be most potent and non-cytotoxic with IC of 0.097 µM against W2 strain of P. falciparum and a selective index of >2000.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2019.04.006DOI Listing
July 2019

Confirmation of 2,4-D resistance and identification of multiple resistance in a Kansas Palmer amaranth (Amaranthus palmeri) population.

Pest Manag Sci 2019 Nov 5;75(11):2925-2933. Epub 2019 Apr 5.

Agricultural Research Center, Kansas State University, Hays, KS, USA.

Background: Amaranthus palmeri S. Wats is among the most problematic annual broadleaf weed species in the USA, including in Kansas. In late summer 2015, seeds of an A. palmeri population (MHR) that had survived field-use rates of 2,4-D were collected from Barton County, KS, USA. The main objectives were to: (i) confirm and characterize 2,4-D resistance in a MHR population; (ii) characterize the resistance profile of the MHR population in relation to a multiple herbicide-susceptible (MHS) population to glyphosate, chlorsulfuron, atrazine, mesotrione, fomesafen; and (iii) determine the effectiveness of alternative POST burndown herbicides for controlling MHR population.

Results: The MHR population had 3.2-fold resistance to 2,4-D. In addition, the MHR population also exhibited multiple resistance to glyphosate (11.8-fold), chlorsulfuron (5.0-fold), atrazine (14.4-fold), and mesotrione (13.4-fold). Furthermore, the MHR population also showed reduced sensitivity to fomesafen (2.3-fold). In a separate study, dicamba with glyphosate, atrazine or fluroxypyr + 2,4-D, and paraquat alone or with atrazine, metribuzin, saflufenacil or 2,4-D provided ≥ 99% injury to the MHR population. Similarly, saflufenacil alone or with atrazine, metribuzin or 2,4-D, and glufosinate alone or with glyphosate + 2,4-D, and glyphosate + dicamba, and a premix of bicyclopyrone + atrazine + mesotrione + S-metolachlor also effectively controlled the MHR population.

Conclusion: This research confirms the first global case of an A. palmeri population from Kansas with multiple resistance to 2,4-D, glyphosate, chlorsulfuron, atrazine and mesotrione, and reduced sensitivity to fomesafen. Dicamba, glufosinate, paraquat, and saflufenacil alone or in tank-mixtures with PRE herbicides effectively controlled this MHR population. © 2019 Society of Chemical Industry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ps.5400DOI Listing
November 2019

Design, synthesis, anti-mycobacterial and cytotoxic evaluation of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates.

Chem Biol Drug Des 2019 07 7;94(1):1300-1305. Epub 2019 Mar 7.

Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab, India.

This manuscript discloses the design and synthesis of a series of C-4 functionalized 1,8-naphthalimide-heterocyclic hydrazide conjugates along with their anti-mycobacterial and cytotoxic evaluation. The present work assumes significance as it describes the first report on the amalgamation of C-4 substituted naphthalimides with various heterocyclic hydrazides. However, contrary to the rationale behind the synthesis of the conjugates, none of them inhibited the growth of Mycobacterium tuberculosis at the tested concentrations though these were non-cytotoxic towards the Vero kidney epithelial cell line.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cbdd.13503DOI Listing
July 2019

Recent developments in biological aspects of chalcones: the odyssey continues.

Expert Opin Drug Discov 2019 03;14(3):249-288

a Department of Chemistry , Guru Nanak Dev University , Amritsar , India.

Introduction: Chalcones are attractive to synthetic chemists because they are easy to prepare, have a large number of replaceable hydrogens, thereby having significant biological potential. Chalcones and their derivatives (carbocyclic as well as heterocyclic) exhibit a range of biological properties including anticancer, antimalarial, antioxidant, anti-inflammatory and anti-tubercular activities. Their promising biological profile, along with their ease of synthetic manipulations, have triggered the design and development of new chalcone derivatives as well as their conjugates with active pharmacophores affording therapeutic templates targeting various diseases. Areas covered: This review focuses on synthesized substituted chalcones as well as chalcone-based molecular conjugates that have been developed between 2015 and 2018. Furthermore, their structure-activity relationships with an emphasis on their mechanism of action and docking studies along with their future therapeutic applications. Expert opinion: A recent upsurge in scientific literature encompassing the synthesis of new chalcone-derivatives as well as its role in ameliorating the activity profiles via amalgamation with other pharmacophores has clearly established the importance of chalcones in present-day drug discovery. As a point, we, the authors, believe that new effective scaffolds can be developed from chalcones with an added advantage of being available at a low cost.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17460441.2019.1573812DOI Listing
March 2019

Correction: Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds.

Dalton Trans 2019 02;48(9):3146

Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab, India.

Correction for 'Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds' by Amandeep Singh et al., Dalton Trans., 2019, DOI: 10.1039/c8dt03440k.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9dt90027fDOI Listing
February 2019

Neurodevelopmental heterogeneity and computational approaches for understanding autism.

Transl Psychiatry 2019 02 4;9(1):63. Epub 2019 Feb 4.

Institute of Child Development, University of Minnesota, Minneapolis, MN, 55455, USA.

In recent years, the emerging field of computational psychiatry has impelled the use of machine learning models as a means to further understand the pathogenesis of multiple clinical disorders. In this paper, we discuss how autism spectrum disorder (ASD) was and continues to be diagnosed in the context of its complex neurodevelopmental heterogeneity. We review machine learning approaches to streamline ASD's diagnostic methods, to discern similarities and differences from comorbid diagnoses, and to follow developmentally variable outcomes. Both supervised machine learning models for classification outcome and unsupervised approaches to identify new dimensions and subgroups are discussed. We provide an illustrative example of how computational analytic methods and a longitudinal design can improve our inferential ability to detect early dysfunctional behaviors that may or may not reach threshold levels for formal diagnoses. Specifically, an unsupervised machine learning approach of anomaly detection is used to illustrate how community samples may be utilized to investigate early autism risk, multidimensional features, and outcome variables. Because ASD symptoms and challenges are not static within individuals across development, computational approaches present a promising method to elucidate subgroups of etiological contributions to phenotype, alternative developmental courses, interactions with biomedical comorbidities, and to predict potential responses to therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-019-0390-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362076PMC
February 2019

Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds.

Dalton Trans 2019 Feb;48(9):2840-2860

Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, Punjab, India.

Two exemplary contributions of organometallics in medicinal chemistry, ferroquine and ferrocifen, which exhibit excellent anti-plasmodial and anti-cancer activities, respectively, have opened a new field called medicinal organometallic chemistry. This field has been gaining significant interest due to the recent upsurge in ferrocene-linked organic frameworks with promising biological potential. The success of ferrocene is due to the sustained efforts by organic medicinal chemists and its inherent stability in air, heat and light, low toxicity, low cost and reversible redox properties. The replacement of the aryl/heteroaryl core with a ferrocene nucleus in organic molecules imparts a significant change not only in their molecular properties, such as solubility and hydro-/lipophilicity, but also improves the activities of bioactive compounds. Ferrocifen (ferrocene analogue of hydroxytamoxifen) possesses the remarkable feature of being anti-proliferative against both the MCF-7 (hormone dependent) and MDA-MB-231 (hormone independent) breast cancer cell lines. Accordingly, this review article is aimed at updating researchers on the recent developments (2014-18) on the synthesis and evaluation of ferrocene-containing bio-active pharmacophores with emphasis on their structure-activity relationship and mechanism of action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8dt03440kDOI Listing
February 2019

Highly Potent 1-1,2,3-Triazole-Tethered Isatin-Metronidazole Conjugates Against Anaerobic Foodborne, Waterborne, and Sexually-Transmitted Protozoal Parasites.

Front Cell Infect Microbiol 2018 30;8:380. Epub 2018 Oct 30.

Department of Chemistry, Guru Nanak Dev University, Amritsar, India.

Parasitic infections like amebiasis, trichomoniasis, and giardiasis are major health threats in tropical and subtropical regions of the world. Metronidazole (MTZ) is the current drug of choice for amebiasis, giardiasis, and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative antimicrobials, a library of 1-1,2,3-triazole-tethered metronidazole-isatin conjugates was synthesized using Huisgen's azide-alkyne cycloaddition reaction and evaluated for their amebicidal, anti-trichomonal, and anti-giardial potential. Most of the synthesized conjugates exhibited activities against , and . While activities against and were comparable to that of the standard drug MTZ, better activities were observed against and . Conjugates and were found to be 2-3-folds more potent than MTZ against and 8-16-folds more potent than MTZ against . Further analysis of these compounds on fungi and bacteria did not show inhibitory activity, demonstrating their specific anti-protozoal properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2018.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218680PMC
September 2019

1-1,2,3-Triazole Tethered Nitroimidazole-Isatin Conjugates: Synthesis, Docking, and Anti-Proliferative Evaluation against Breast Cancer.

ACS Omega 2018 Sep 27;3(9):12106-12113. Epub 2018 Sep 27.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.

1-1,2,3-Triazole tethered imidazole-isatin and imidazole-isatin-thiosemicarbazone conjugates were synthesized and evaluated against MCF-7 and MDA-MB-231 cell lines. Antiproliferative activities of the synthesized conjugates revealed an optimum combination of longer alkyl chain length as spacer and a halogen-substituent on the isatin ring as a pre-requisite for good activity. The compound with an optimum combination of chloro-substituent at C-5 position of isatin ring and a butyl chain length proved to be most active and noncytotoxic with IC of 54.25 and 26.12 μM against MCF-7 and MDA-MB-231 cell lines, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.8b01513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175498PMC
September 2018

Synthesis and Preliminary Antimicrobial Analysis of Isatin-Ferrocene and Isatin-Ferrocenyl Chalcone Conjugates.

ACS Omega 2018 May 30;3(5):5808-5813. Epub 2018 May 30.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India.

In this study, we outline the synthesis of isatin-ferrocenyl chalcone and 1-1,2,3-triazole-tethered isatin-ferrocene conjugates along with their antimicrobial evaluation against the human mucosal pathogen . The introduction of a triazole ring among the synthesized conjugates improved the activity profiles with most of the compounds in the library, exhibiting 100% growth inhibition in a preliminary susceptibility screen at 100 μM. IC determination of the most potent compounds in the set revealed an inhibitory range between 2 and 13 μM. Normal flora microbiome are unaffected by these compounds, suggesting that these may be new chemical scaffolds for the discovery of new drugs against trichomonad infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.8b00553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045481PMC
May 2018

Azide-Alkyne Cycloaddition En Route to 1-1,2,3-Triazole-Tethered Isatin-Ferrocene, Ferrocenylmethoxy-Isatin, and Isatin-Ferrocenylchalcone Conjugates: Synthesis and Antiproliferative Evaluation.

ACS Omega 2018 Jan 30;3(1):1263-1268. Epub 2018 Jan 30.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.

Diverse series of isatin-ferrocene conjugates were synthesized via Cu-promoted azide-alkyne cycloaddition reaction with an aim of probing their antiproliferative structure-activity relationship against MCF-7 (estrogen receptor positive) and MDA-MB-231 (triple negative) cell lines. Among the synthesized conjugates, isatin-ferrocenes proved to be more potent against MCF-7, whereas ferrocenylmethoxy-isatins exhibited activity against MDA-MB-231 cell lines. However, the introduction of chalcone moiety among these hybrids resulted in the complete loss of activity against the tested cell lines, as evident by isatin-ferrocenylchalcones. The conjugates and proved to be the most potent among the series against MCF-7 and MDA-MB-213 cell lines, exhibiting IC values of 31.62 and 20.26 μM, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsomega.7b01755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044575PMC
January 2018

Alkylated/aminated nitroimidazoles and nitroimidazole-7-chloroquinoline conjugates: Synthesis and anti-mycobacterial evaluation.

Bioorg Med Chem Lett 2018 05 8;28(8):1309-1312. Epub 2018 Mar 8.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India. Electronic address:

The success in exploring anti-tubercular potency of nitroimidazole and quinoline, the core moieties of recently approved anti-tubercular drugs instigated us to synthesize a series of alkylated/aminated 2-methyl-5-nitroimidazoles and nitroimidazole-7-chloroquinoline conjugates and to evaluate them for their activities against Mycobacterium tuberculosis as well as for their cytotoxicity towards the J774 murine macrophage cell line. Although the synthesized compounds did not surpass the activity of the standard drug Isoniazid, they have appreciable activities with minimal cytotoxicity. The synthesized nitroimidazole-7-chloroquinoline conjugate, 11c, having butyl chain as linker, proved to be the most potent among the series with an MIC value of 2.2 μg/mL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2018.03.021DOI Listing
May 2018

Design, Synthesis and Preliminary Antimicrobial Evaluation of -Alkyl Chain Tethered C-5 Functionalized Bis-Isatins.

Medchemcomm 2017 19;8(10):1982-1992. Epub 2017 Sep 19.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.

A series of -alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound , with an optimal combination of bromo-substituent at the C-5 position of isatin ring along with propyl chain linker being most active among the synthesized series exhibiting an IC value of 3.72 μM against while exhibited an IC value of 14.8 μM against , more effective than the standard drug Miltefosine. The compound with an octyl spacer length was the most potent among the series against with an IC of 18.4 μM while exhibited an IC of 23 μM against . This library was also screened against the fungal pathogen . A number of the compounds demonstrated potency against this fungus, illustrating a possible broad-spectrum activity. Furthermore, an evaluation of these synthesized compounds against a panel of normal flora bacteria revealed them to be non-cytotoxic, demonstrating the selectivity of these compounds. This observation, in combination with previous studies that isatin is non-toxic to humans, presents a new possible scaffold for drug discovery against these important protozoal pathogens of humans and animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/C7MD00434FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810968PMC
September 2017

Microwave-promoted facile access to 4-aminoquinoline-phthalimides: Synthesis and anti-plasmodial evaluation.

Eur J Med Chem 2018 Jan 16;143:150-156. Epub 2017 Nov 16.

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India. Electronic address:

Microwave promoted high yielding synthesis of 4-aminoquinoline-phthalimides was developed with an aim to evaluate their anti-plasmodial potential. The scaffolds with longer spacer length (n = 6, 8) between two pharmacophores and a halogen substituent on the phthalimide ring displayed good antiplasmodial activity. Compound 5w, with an optimum combination of hexyl chain as spacer along with a tetra-bromophthalimide ring proved to be most potent and non-cytotoxic among the series exhibiting an IC value of 0.10 μM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2017.11.033DOI Listing
January 2018
-->