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Diwan S. Rawat - One of the best experts on this subject based on the ideXlab platform.
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synthesis antimalarial activity heme binding and docking studies of n substituted 4 Aminoquinoline pyrimidine molecular hybrids
European Journal of Medicinal Chemistry, 2017Co-Authors: Shiv Shyam Maurya, Shabana I. Khan, Deepak Kumar, Aparna Bahuguna, Diwan S. RawatAbstract:Abstract A series of novel N-substituted 4-Aminoquinoline-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.
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Design, synthesis and evaluation of 4-Aminoquinoline-purine hybrids as potential antiplasmodial agents.
European Journal of Medicinal Chemistry, 2016Co-Authors: P. Linga Reddy, Shabana I. Khan, Mohit Tripathi, Prija Ponnan, Diwan S. RawatAbstract:Abstract A novel series of 4-Aminoquinoline-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 4-Aminoquinoline 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.
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4 Aminoquinoline pyrimidine aminoalkanols synthesis in vitro antimalarial activity docking studies and adme predictions
New Journal of Chemistry, 2015Co-Authors: Mohit Tripathi, Shabana I. Khan, Prija Ponnan, Anuj Thakur, Diwan S. RawatAbstract:Twenty-four new 4-Aminoquinoline-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.
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4 Aminoquinoline pyrimidine hybrids synthesis antimalarial activity heme binding and docking studies
European Journal of Medicinal Chemistry, 2015Co-Authors: Deepak Kumar, Shabana I. Khan, Babu L Tekwani, Prija Ponnan, Diwan S. RawatAbstract:Abstract A series of novel 4-Aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro 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. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction.
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4 Aminoquinoline based molecular hybrids as antimalarials an overview
Current Topics in Medicinal Chemistry, 2014Co-Authors: Sunny Manohar, Mohit Tripathi, Diwan S. RawatAbstract: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 4-Aminoquinoline 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 4-Aminoquinoline based molecular hybrids as potential antimalarial agents. It also presents a brief and simplified story on the development of 4-Aminoquinolines as a mainstay in malarial research programmes.
Shabana I. Khan - One of the best experts on this subject based on the ideXlab platform.
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synthesis antimalarial activity heme binding and docking studies of n substituted 4 Aminoquinoline pyrimidine molecular hybrids
European Journal of Medicinal Chemistry, 2017Co-Authors: Shiv Shyam Maurya, Shabana I. Khan, Deepak Kumar, Aparna Bahuguna, Diwan S. RawatAbstract:Abstract A series of novel N-substituted 4-Aminoquinoline-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.
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Design, synthesis and evaluation of 4-Aminoquinoline-purine hybrids as potential antiplasmodial agents.
European Journal of Medicinal Chemistry, 2016Co-Authors: P. Linga Reddy, Shabana I. Khan, Mohit Tripathi, Prija Ponnan, Diwan S. RawatAbstract:Abstract A novel series of 4-Aminoquinoline-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 4-Aminoquinoline 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.
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4 Aminoquinoline pyrimidine aminoalkanols synthesis in vitro antimalarial activity docking studies and adme predictions
New Journal of Chemistry, 2015Co-Authors: Mohit Tripathi, Shabana I. Khan, Prija Ponnan, Anuj Thakur, Diwan S. RawatAbstract:Twenty-four new 4-Aminoquinoline-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.
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4 Aminoquinoline pyrimidine hybrids synthesis antimalarial activity heme binding and docking studies
European Journal of Medicinal Chemistry, 2015Co-Authors: Deepak Kumar, Shabana I. Khan, Babu L Tekwani, Prija Ponnan, Diwan S. RawatAbstract:Abstract A series of novel 4-Aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro 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. Selected compound 7g exhibited significant suppression of parasitemia in the in vivo assay. The heme binding studies were conducted to determine the mode of action of these hybrid molecules. These compounds form a stable 1:1 complex with hematin suggesting that heme may be one of the possible targets of these hybrids. The interaction of these conjugate hybrids was also investigated by the molecular docking studies in the binding site of PfDHFR. The pharmacokinetic property analysis of best active compounds was also studied using ADMET prediction.
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synthesis of piperazine tethered 4 Aminoquinoline pyrimidine hybrids as potent antimalarial agents
RSC Advances, 2014Co-Authors: Anuj Thakur, Shabana I. Khan, Diwan S. RawatAbstract:A series of 4-Aminoquinoline-pyrimidine hybrids linked through piperazine were synthesized and evaluated for their in vitro antimalarial activity against chloroquine (CQ)-sensitive and chloroquine (CQ)-resistant strains of Plasmodium falciparum and cytotoxicity against mammalian cell line (Vero). Nine compounds (5e, 5f, 5g, 5h, 5i, 5j, 5k, 7a, 7d) displayed good antimalarial activity against both the strains out of which compound 5j was the most potent with IC50 values in the range of 0.13–0.14 μM. The antimalarial activity of 5j was 2.5 fold stronger than chloroquine in the CQ-resistant strain of P. falciparum. None of the compounds were found to be cytotoxic against Vero cells. The X-ray crystal structure of one of the compounds was also determined.
Sunny Manohar - One of the best experts on this subject based on the ideXlab platform.
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4 Aminoquinoline based molecular hybrids as antimalarials an overview
Current Topics in Medicinal Chemistry, 2014Co-Authors: Sunny Manohar, Mohit Tripathi, Diwan S. RawatAbstract: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 4-Aminoquinoline 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 4-Aminoquinoline based molecular hybrids as potential antimalarial agents. It also presents a brief and simplified story on the development of 4-Aminoquinolines as a mainstay in malarial research programmes.
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anticancer activity of 4 Aminoquinoline triazine based molecular hybrids
RSC Advances, 2014Co-Authors: Sunny Manohar, Antonella Pepe, Christian Velez E Gerena, Beatriz Zayas, Sanjay V Malhotra, Diwan S. RawatAbstract:In this study the potential for anticancer activity of 4-Aminoquinoline-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.
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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, 2013Co-Authors: Sunny Manohar, Shabana I. Khan, Diwan S. RawatAbstract:: 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-4-Aminoquinoline-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.
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novel 4 Aminoquinoline pyrimidine based hybrids with improved in vitro and in vivo antimalarial activity
ACS Medicinal Chemistry Letters, 2012Co-Authors: Sunny Manohar, Shabana I. Khan, Babu L Tekwani, Chinna U Rajesh, Diwan S. RawatAbstract:A class of hybrid molecules consisting of 4-Aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay. Eleven hybrids showed better antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum in comparison to standard drug CQ. Four molecules were more potent (7–8-fold) than CQ in D6 strain, and eight molecules were found to be 5–25-fold more active against resistant strain (W2). Several compounds did not show any cytotoxicity up to a high concentration (60 μM), others exhibited mild toxicities, but the selective index for the antimalarial activity was very high for most of these hybrids. Two compounds selected for in vivo evaluation have shown excellent activity (po) in a mouse model of Plasmodium berghei without any apparent toxicity. The X-ray crystal structure of one of the compounds was also determined.
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synthesis of 4 Aminoquinoline 1 2 3 triazole and 4 Aminoquinoline 1 2 3 triazole 1 3 5 triazine hybrids as potential antimalarial agents
Chemical Biology & Drug Design, 2011Co-Authors: Sunny Manohar, Shabana I. Khan, Diwan S. RawatAbstract:: We report herein synthesis of a series of 4-Aminoquinoline-1,2,3-triazole and 4-Aminoquinoline-1,2,3-triazole-1,3,5-triazine hybrids and evaluate their antimalarial activity against D6 and W2 strains of Plasmodium falciparum. To study the structure-activity relationship of substituted 4-Aminoquinoline-based hybrids, 34 structurally diverse compounds were synthesized and tested against D6 and W2 strains of P. falciparum. Some of the compounds have shown promising antimalarial activity without toxicity against Vero cells.
Udaya Pratap Singh - One of the best experts on this subject based on the ideXlab platform.
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synthesis antimalarial activity and molecular docking of hybrid 4 Aminoquinoline 1 3 5 triazine derivatives
Experimental Parasitology, 2015Co-Authors: Hans Raj Bhat, Anil Prakash, Udaya Pratap Singh, Anjali Thakur, Surajit Kumar Ghosh, Kabita Gogoi, Ramendra K SinghAbstract:A series of novel hybrid 4-Aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS).
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4 Aminoquinoline 1 3 5 triazine design synthesis in vitro antimalarial activity and docking studies
New Journal of Chemistry, 2013Co-Authors: Hans Raj Bhat, Anil Prakash, Udaya Pratap Singh, Surajit Kumar Ghosh, Kabita Gogoi, Prashant Gahtori, Ramendra K SinghAbstract:A series of hybrid 4-Aminoquinoline 1,3,5-triazine derivatives was synthesized and their chemical structure were confirmed by 1H-NMR, 13C-NMR, FT-IR and mass spectrometric analyses. In vitro antimalarial activity of these compounds was evaluated against chloroquine-sensitive (3D-7) and chloroquine resistant (RKL-2) strains of P. falciparum. Results showed that all compounds had considerable antimalarial activity against both the strains and further docking studies were performed on both wild type (1J3I.pdb) and quadruple mutant (N51I, C59R, S108 N, I164L, 3QG2.pdb) pf-DHFR-TS to quantify the structural parameter necessary for the activity.
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development of 4 Aminoquinoline 1 3 5 triazine conjugates as potent antibacterial agent through facile synthetic route
Medicinal Chemistry Research, 2013Co-Authors: Hans Raj Bhat, Udaya Pratap Singh, Surajit Kumar Ghosh, Pankaj Kumar PandeyAbstract:A series of novel hybrid 4-Aminoquinoline-1,3,5-triazine derivatives were developed and subsequently tested against representative Gram-positive and Gram-negative microorganisms for determination of their antibacterial activity. Screening results indicate that, title molecule exhibit moderate to potent activity in comparison to standard. These hybrid derivatives were synthesized through a facile synthetic routes and structure of reaction intermediates as well as target molecules were recognised with the aid of various spectroscopic techniques viz., FTIR, NMR, mass and elemental analysis.
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antimalarial activity and docking studies of novel bi functional hybrids derived from 4 Aminoquinoline and 1 3 5 triazine against wild and mutant malaria parasites as pf dhfr inhibitor
RSC Advances, 2013Co-Authors: Hans Raj Bhat, Anil Prakash, Udaya Pratap Singh, Surajit Kumar Ghosh, Kabita Gogoi, Prashant Gahtori, Ramendra K SinghAbstract:Bi-functional conjugates comprised of 4-Aminoquinoline and 1,3,5-triazine were synthesized through facile synthetic routes. These compounds were rigorously screened for determination of their antimalarial activity against wild and mutant cultured Plasmodium falciparum. The results disclosed that the conjugates have considerable antimalarial activity against both wild and mutant parasites with marked variation on changing the pattern of substitutions. The observed activity profiles were additionally substantiated by docking studies on both wild and quadruple mutant P. falciparum dihydrofolate reductase thymidylate synthase (pf-DHFR-TS).
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discovery of potent novel antibacterial hybrid conjugates from 4 Aminoquinoline and 1 3 5 triazine design synthesis and antibacterial evaluation
RSC Advances, 2012Co-Authors: Hans Raj Bhat, Satish K Gupta, Udaya Pratap SinghAbstract:A series of hybrid 4-Aminoquinoline-1,3,5-triazine conjugates 7a–g were synthesized and evaluated for their in vitro antibacterial activity against several Gram-positive and Gram-negative microorganisms. The entire set of target compounds displayed potent to excellent activity against human disease causing pathogens with reference to Levofloxacin as a standard drug.
Vipan Kumar - One of the best experts on this subject based on the ideXlab platform.
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synthesis anti plasmodial and cytotoxic evaluation of 1h 1 2 3 triazole acyl hydrazide integrated tetrahydro β carboline 4 Aminoquinoline conjugates
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Bharvi Sharma, Philip J Rosenthal, Simranjeet Kaur, Jenny Legac, Vipan KumarAbstract:Abstract 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.
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microwave promoted facile access to 4 Aminoquinoline phthalimides synthesis and anti plasmodial evaluation
European Journal of Medicinal Chemistry, 2018Co-Authors: Anu Rani, Amandeep Singh, Philip J Rosenthal, Vipan KumarAbstract:Abstract 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 IC50 value of 0.10 μM.
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4 Aminoquinoline chalcone n acetylpyrazoline conjugates synthesis and antiplasmodial evaluation
European Journal of Medicinal Chemistry, 2017Co-Authors: S Kumar, Anu Saini, Philip J Rosenthal, Vipan KumarAbstract:Abstract 1H-1,2,3-triazole linked 4-Aminoquinoline-chalcone/-N-acetylpyrazoline conjugates were synthesized and evaluated against cultured chloroquine (CQ) resistant strain. Antiplasmodial activities of the synthesized conjugates revealed dependence of activity on the length of the alkyl chain as well as on the presence of methoxy substituents on ring A/ring B of the chalcone. The most potent and non-cytotoxic conjugate showed comparable antiplasmodial activity with that of CQ, with an IC50 value of 53.7 nM.
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azide alkyne cycloaddition en route to 4 Aminoquinoline ferrocenylchalcone conjugates synthesis and anti tb evaluation
Future Medicinal Chemistry, 2017Co-Authors: Amandeep Singh, Albertus Viljoen, Laurent Kremer, Vipan KumarAbstract:Aim: Tuberculosis is responsible for 9.6 million infections and 1.5 million deaths in 2015. The development of multidrug-resistant and extensively drug-resistant strains has impeded the development of effective antitubercular therapy. Results/methodology: The present manuscript describes the synthesis of a series of 4-Aminoquinoline–ferrocenylchalcone conjugates via Cu-promoted Huisgen’s azide–alkyne cycloaddition reaction and evaluation of their antitubercular activities against mc26230 strain of Mycobacterium tuberculosis. The conjugate 11j proved to be the most potent of the synthesized conjugates with a minimum inhibitory concentration (MIC99) value of 30 μM and proved to be noncytotoxic against HeLa cells. Conclusion: The synthesized conjugates can act as starting point for the development of new antitubercular agents. Synthesis and antitubercular evaluation of 1H-1,2,3-triazole-tethered 4-Aminoquinoline–ferrocenylchalcone conjugates.
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piperazine linked 4 Aminoquinoline chalcone ferrocenyl chalcone conjugates synthesis and antiplasmodial evaluation
Chemical Biology & Drug Design, 2017Co-Authors: Amandeep Singh, Philip J Rosenthal, Anu Rani, Vipan KumarAbstract:A series of piperazine-linked 4-Aminoquinoline-chalcone/ferrocenyl-chalcone conjugates were prepared with a view to evaluate their activities against Plasmodium falciparum. The synthesized conjugates had in vitro IC50 values from 0.41 to 2.38 μm against chloroquine-resistant and mefloquine-sensitive W2 strain of P. falciparum. The submicromolar activities of most of the synthesized conjugates suggest that such molecular frameworks can act as therapeutic templates for the design and synthesis of new antimalarials.
