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4 Aminoquinoline

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Diwan S. Rawat – 1st expert on this subject based on the ideXlab platform

  • synthesis antimalarial activity heme binding and docking studies of n substituted 4 Aminoquinoline pyrimidine molecular hybrids
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Shiv Shyam Maurya, Deepak Kumar, Shabana I. Khan, Aparna Bahuguna, Diwan S. Rawat

    Abstract:

    Abstract A series of novel N-substituted 4Aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction.

  • Design, synthesis and evaluation of 4Aminoquinoline-purine hybrids as potential antiplasmodial agents.
    European Journal of Medicinal Chemistry, 2016
    Co-Authors: P. Linga Reddy, Mohit Tripathi, Shabana I. Khan, Prija Ponnan, Diwan S. Rawat

    Abstract:

    Abstract A novel series of 4Aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4Aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08 μM) compared to the reference drug CQ (IC50: 0.5 μM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86 μM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior.

  • 4 Aminoquinoline pyrimidine aminoalkanols synthesis in vitro antimalarial activity docking studies and adme predictions
    New Journal of Chemistry, 2015
    Co-Authors: Mohit Tripathi, Shabana I. Khan, Prija Ponnan, Anuj Thakur, Diwan S. Rawat

    Abstract:

    Twenty-four new 4Aminoquinoline-pyrimidine hybrids containing a terminal aliphatic amino-alcohol chain were synthesized and assessed for their antimalarial activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum. All of the compounds displayed potent antiplasmodial activities (IC50 values in the range of 0.05–10.47 μM) with no appreciable cytotoxicity towards mammalian cells, up to the highest tested concentration of 12 μM. Molecular docking studies of the most active compounds (8b–8f, 8u and 8v) with both wild type and quadruple mutant Pf-DHFR-TS were performed, which exhibited interactions comparable to conventional folate inhibitors. ADME predictions also revealed favourable pharmacokinetic parameters for the synthesized hybrids, which warrants their suitability for development as potent antimalarials.

Shabana I. Khan – 2nd expert on this subject based on the ideXlab platform

  • synthesis antimalarial activity heme binding and docking studies of n substituted 4 Aminoquinoline pyrimidine molecular hybrids
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Shiv Shyam Maurya, Deepak Kumar, Shabana I. Khan, Aparna Bahuguna, Diwan S. Rawat

    Abstract:

    Abstract A series of novel N-substituted 4Aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction.

  • Design, synthesis and evaluation of 4Aminoquinoline-purine hybrids as potential antiplasmodial agents.
    European Journal of Medicinal Chemistry, 2016
    Co-Authors: P. Linga Reddy, Mohit Tripathi, Shabana I. Khan, Prija Ponnan, Diwan S. Rawat

    Abstract:

    Abstract A novel series of 4Aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4Aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08 μM) compared to the reference drug CQ (IC50: 0.5 μM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86 μM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior.

  • 4 Aminoquinoline pyrimidine aminoalkanols synthesis in vitro antimalarial activity docking studies and adme predictions
    New Journal of Chemistry, 2015
    Co-Authors: Mohit Tripathi, Shabana I. Khan, Prija Ponnan, Anuj Thakur, Diwan S. Rawat

    Abstract:

    Twenty-four new 4Aminoquinoline-pyrimidine hybrids containing a terminal aliphatic amino-alcohol chain were synthesized and assessed for their antimalarial activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum. All of the compounds displayed potent antiplasmodial activities (IC50 values in the range of 0.05–10.47 μM) with no appreciable cytotoxicity towards mammalian cells, up to the highest tested concentration of 12 μM. Molecular docking studies of the most active compounds (8b–8f, 8u and 8v) with both wild type and quadruple mutant Pf-DHFR-TS were performed, which exhibited interactions comparable to conventional folate inhibitors. ADME predictions also revealed favourable pharmacokinetic parameters for the synthesized hybrids, which warrants their suitability for development as potent antimalarials.

Sunny Manohar – 3rd expert on this subject based on the ideXlab platform

  • 4 Aminoquinoline based molecular hybrids as antimalarials an overview
    Current Topics in Medicinal Chemistry, 2014
    Co-Authors: Sunny Manohar, Mohit Tripathi, Diwan S. Rawat

    Abstract:

    In recent times, the novel concept of generating hybrid molecules by pharmacophoric hybridisation approach is
    fast becoming an alternative to other existing strategies of drug development. These hybrids also known as ‘dual drugs’ or
    ‘double drugs’ are especially found to be effective in overcoming drug resistance problems. Towards this end, a lot of effort
    has been put for generating 4Aminoquinoline based hybrid molecules as next generation antimalarial drugs effective
    in malarial chemotherapy. This short review deals about the recent advances carried in the field of 4Aminoquinoline
    based molecular hybrids as potential antimalarial agents. It also presents a brief and simplified story on the development
    of 4Aminoquinolines as a mainstay in malarial research programmes.

  • anticancer activity of 4 Aminoquinoline triazine based molecular hybrids
    RSC Advances, 2014
    Co-Authors: Sunny Manohar, Antonella Pepe, Christian Velez E Gerena, Beatriz Zayas, Sanjay V Malhotra, Diwan S. Rawat

    Abstract:

    In this study the potential for anticancer activity of 4Aminoquinoline-triazine based hybrids has been investigated on 60 human cancer cell lines (NCI 60). The representative compounds show activity on a range of cell lines and apoptosis as the mode of growth inhibition.

  • 4 Aminoquinoline triazine based hybrids with improved in vitro antimalarial activity against cq sensitive and cq resistant strains of plasmodium falciparum
    Chemical Biology & Drug Design, 2013
    Co-Authors: Sunny Manohar, Shabana I. Khan, Diwan S. Rawat

    Abstract:

    : A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-chloroquinolines yielded a series of new 7-chloro-4Aminoquinoline-triazine hybrids exhibiting high in vitro activity against W2 (chloroquine-resistant) and D6 (chloroquine-sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine-resistant strains (W2 clone) of P. falciparum.