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Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study

Published online by Cambridge University Press:  27 May 2016

SWAROOP KUMAR PANDEY ,
SUBHASISH BISWAS ,
SARIKA GUNJAN ,
BHAVANA SINGH CHAUHAN ,
SUNIL KUMAR SINGH ,
KUMKUM SRIVASTAVA ,
SARIKA SINGH ,
SANJAY BATRA  and
RENU TRIPATHI
SWAROOP KUMAR PANDEY
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
SUBHASISH BISWAS
Affiliation:
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
SARIKA GUNJAN
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
BHAVANA SINGH CHAUHAN
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
SUNIL KUMAR SINGH
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
KUMKUM SRIVASTAVA
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India Academy of Scientific and Innovative Research, New Delhi 110025, India
SARIKA SINGH
Affiliation:
Division of Toxicology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
SANJAY BATRA*
Affiliation:
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India Academy of Scientific and Innovative Research, New Delhi 110025, India
RENU TRIPATHI*
Affiliation:
Division of Parasitology, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India Academy of Scientific and Innovative Research, New Delhi 110025, India
*
*Corresponding authors: Division of Parasitology, CSIR-CDRI, Lucknow (India) 220031, India. E-mail: renu1113@rediffmail.com and Medicinal and Process Chemistry Division, CSIR-CDRI, Lucknow 220031, India. E-mail: batra_san@yahoo.co.uk, s_batra@cdri.res.in
*Corresponding authors: Division of Parasitology, CSIR-CDRI, Lucknow (India) 220031, India. E-mail: renu1113@rediffmail.com and Medicinal and Process Chemistry Division, CSIR-CDRI, Lucknow 220031, India. E-mail: batra_san@yahoo.co.uk, s_batra@cdri.res.in
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Summary

Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development.

Keywords

Malariamultidrug resistantpyrrolidine-acridine hybridACTcombination therapypharmacodynamics
Type
Research Article
Information
Parasitology , Volume 143 , Issue 11 , September 2016 , pp. 1421 - 1432
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Copyright
Copyright © Cambridge University Press 2016 

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