title: Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study.
abstract: 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.
authors.affiliation: Division of Parasitology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Swaroop Kumar
authors.initials: SK
authors.lastname: Pandey
authors.affiliation: Medicinal and Process Chemistry Division,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Subhasish
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Division of Parasitology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Gunjan
authors.affiliation: Division of Parasitology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Bhavana Singh
authors.initials: BS
authors.lastname: Chauhan
authors.affiliation: Division of Parasitology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Division of Parasitology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Srivastava
authors.affiliation: Division of Toxicology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry Division,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Batra
authors.affiliation: Division of Parasitology,CSIR-Central Drug Research Institute,Sector 10,Jankipuram Extension,Sitapur Road,Lucknow 226031,India.
authors.forename: Renu
authors.initials: R
authors.lastname: Tripathi
mesh_terms: D000166:Acridines / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D007928:Lethal Dose 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000166:Acridines; D000962:Antimalarials; D037621:Artemisinins; D011759:Pyrrolidines; C031327:artemisinin; D000077549:Artemether; C032519:pyrrolidine
keywords: ACT; Malaria; combination therapy; multidrug resistant; pharmacodynamics; pyrrolidine-acridine hybrid