Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives

• Published in: Chemical biology & drug design 2017-09, Vol.90 (3), p.464-472
• Main Authors: Pereira, Glaécia A. N., Souza, Gisele C., Santos, Lourivaldo S., Barata, Lauro E. S., Meneses, Carla C. F., Krettli, Antoniana U., Daniel‐Ribeiro, Cláudio Tadeu, Alves, Cláudio Nahum
• Format: Article
• Language: English
• Subjects: Antimalarials - chemical synthesis; Antimalarials - metabolism; Antimalarials - pharmacology; antiplasmodial activity; Binding Sites; Cell Survival - drug effects; Chloroquine - pharmacology; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; docking; Drug Resistance - drug effects; falcipain‐2; Hep G2 Cells; Humans; Hydrogen Bonding; Lignans - chemistry; Lignans - metabolism; Lignans - pharmacology; Molecular Docking Simulation; neolignan derivatives; Plasmodium falciparum - drug effects; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Static Electricity; Structure-Activity Relationship
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12968

The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine‐resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and anti‐HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain‐2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine‐resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs. Synthesis and docking studies of new neolignan derivatives with antimalarial activity.