title: Design, synthesis and biological evaluation of functionalized phthalimides: a new class of antimalarials and inhibitors of falcipain-2, a major hemoglobinase of malaria parasite.
abstract: Phthalimides functionalized with cyclic amines were synthesized, characterized and screened for their in vitro antimalarial efficacy against Plasmodium falciparum (Pf3D7). Of all the listed phthalimides evaluated, 14 and 24 were identified as potent antimalarial agents as advocated by assessment of their ability to inhibit [(3)H] hypoxanthine incorporation in the nucleic acid of parasites. In addition, phthalimides 14 and 24 were incubated for 60 and 90h and an enhanced antimalarial effect was noticed with increase in time to great extent. A reduction in IC50 values was observed with increase in exposure time of the parasite to the compounds. A symmetric phthalimide, 24 possessing piperazine as linker unit was identified as the most potent antimalarial agent with IC50 values of 5.97±0.78, 2.0±1.09 and 1.1±0.75μM on incubation period of 42, 60 and 90h, respectively. The abnormal morphologies such as delay in developmental stages, growth arrest and condensed nuclei of parasite were observed with the aid of microscopic studies upon exposure with 14 and 24. The evaluation of 14 and 24 against chloroquine resistant strain, (Pf7GB) of P. falciparum afforded IC50 values, 13.29±1.20 and 7.21±0.98μM, respectively. The combination of 24 with artemisinin (ART) showed enhanced killing of parasite against Pf3D7. Further, all phthalimides were evaluated for their activity against falcipain-2 (FP2), a major hemoglobinase of malarial parasite. The enzymatic assay afforded 6 as most active member against FP2. To the best of our knowledge this is the initial study represents phthalimide protected amino acids functionalized with cyclic amines as potent antimalarial agents.
authors.affiliation: Bio-organic Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110 021, India.
authors.forename: Vinoth
authors.initials: V
authors.lastname: Rajendran
authors.affiliation: National Institute of Malaria Research, Host-Parasite Interaction Biology Group, Lab. No. 219, Sector-8 Dwarka, New Delhi 110077, India.
authors.forename: Akansha
authors.initials: A
authors.lastname: Pant
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110 021, India.
authors.forename: Prahlad C
authors.initials: PC
authors.lastname: Ghosh
authors.affiliation: Bioinformatics Infrastructure Facility, Sri Venkateswara College, University of Delhi South Campus, New Delhi 110 021, India.
authors.forename: Neelu
authors.initials: N
authors.lastname: Singh
authors.affiliation: Bioinformatics Infrastructure Facility, Sri Venkateswara College, University of Delhi South Campus, New Delhi 110 021, India.
authors.forename: N
authors.initials: N
authors.lastname: Latha
authors.affiliation: Department of Zoology, Smt. Chandibai Himathmal Mansukhani College (University of Mumbai), Ulhasnagar, Thane, Maharashtra 421 003, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Garg
authors.affiliation: National Institute of Malaria Research, Host-Parasite Interaction Biology Group, Lab. No. 219, Sector-8 Dwarka, New Delhi 110077, India.
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Pandey
authors.affiliation: Bio-organic Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India.
authors.forename: Brajendra K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Bio-organic Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India; Department of Chemistry, Hans Raj College, University of Delhi, Delhi 110 007, India. Electronic address: brathi@svc.ac.in.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Rathi
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000382:microbiology; D062105:Molecular Docking Simulation; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D010797:Phthalimides; D010879:Piperazines; D003546:Cysteine Endopeptidases; C416224:falcipain 2
keywords: Docking; Falcipain-2; Phthalimides; Piperazine; Plasmodium falciparum