TY - JOUR
T1 - Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition
AU - Sharma, Kalicharan
AU - Shrivastava, Apeksha
AU - Mehra, Ram N.
AU - Deora, Girdhar S.
AU - Alam, Mohammad M.
AU - Zaman, Mohammad S.
AU - Akhter, Mymoona
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain-2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R-01 (0.69 μM), R-04 (1.60 μM), and R-08 (1.61 μM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain-2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein-ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine.
AB - Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain-2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R-01 (0.69 μM), R-04 (1.60 μM), and R-08 (1.61 μM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain-2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein-ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine.
KW - antimalarial agents
KW - benzimidazole acrylonitriles
KW - falcipain-2 inhibitors
KW - hemozoin formation inhibitors
KW - Plasmodium falciparum
UR - http://www.scopus.com/inward/record.url?scp=85040176199&partnerID=8YFLogxK
U2 - 10.1002/ardp.201700251
DO - 10.1002/ardp.201700251
M3 - Article
AN - SCOPUS:85040176199
SN - 1521-4184
VL - 351
JO - Archiv der Pharmazie
JF - Archiv der Pharmazie
IS - 1
M1 - 1700251
ER -