Hydroxyethylamine Based Phthalimides as New Class of Plasmepsin Hits: Design, Synthesis and Antimalarial Evaluation.
A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (Ki: 3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development.
Bioorganic Research Laboratory, Department of Chemistry, University of Delhi, Delhi, India.
Anil K
AK
Singh
Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India.
Sumit
S
Rathore
Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, P.O. Box 100245, Gainesville, FL, United States of America.
Yan
Y
Tang
Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, P.O. Box 100245, Gainesville, FL, United States of America.
Nathan E
NE
Goldfarb
Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, P.O. Box 100245, Gainesville, FL, United States of America.
Ben M
BM
Dunn
Department of Biochemistry, University of Delhi South Campus, Dhaula Kuan, New Delhi, India.
Vinoth
V
Rajendran
Department of Biochemistry, University of Delhi South Campus, Dhaula Kuan, New Delhi, India.
Prahlad C
PC
Ghosh
Bioinformatics Center, Sri Venkateswara College, University of Delhi South Campus, Dhaula Kuan, New Delhi, India.
Neelu
N
Singh
Bioinformatics Center, Sri Venkateswara College, University of Delhi South Campus, Dhaula Kuan, New Delhi, India.
N
N
Latha
Bioorganic Research Laboratory, Department of Chemistry, University of Delhi, Delhi, India.
Brajendra K
BK
Singh
Department of Internal Medicine, 1 University of New Mexico, Albuquerque, New Mexico, United States of America.
Manmeet
M
Rawat
Bioorganic Research Laboratory, Department of Chemistry, University of Delhi, Delhi, India.
Brijesh
B
Rathi
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D000962:Antimalarials; D010797:Phthalimides; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin