Synthesis and Anti‐Plasmodium Activity of Benzimidazole Analogues Structurally Related to Astemizole

Abstract

A series of compounds structurally related to astemizole were designed and synthesized with the goal of determining their anti-Plasmodium activity. Several modifications of the astemizole structure, namely the removal of the 4-fluorobenzyl and/or 4-methoxyphenethyl moieties, substitution of the benzene ring of the benzimidazole scaffold, replacement of the fluorine atom in the 4-fluorobenzyl group, and variation of the 4-aminopiperidine moiety, were explored. In vitro evaluation of the anti-Plasmodium activity of these compounds using the ItG strain showed that astemizole and some of its structurally similar derivatives have IC50 values in the nanomolar range and exhibit toxicity towards the parasite over Chinese ovarian hamster (CHO) cells with a selectivity as high as 200. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 in the benzimidazole moiety are two modifications that resulted in potent and selective antimalarials based on astemizole.

Importance of Fluorine in Benzazole Compounds

“…Benzimidazole is a popular nucleus in structural manipulation in medicinal chemistry and has been intensively discussed in the literature [ 19 , 21 , 22 , 23 , 24 ] and many benzimidazoles are reported to show anthelmintic [ 25 , 26 ], antimicrobial [ 27 , 28 , 29 , 30 , 31 , 32 ], anti-HIV [ 33 , 34 , 35 ], antiviral [ 36 , 37 ], anti-inflammatory [ 38 , 39 ], anticancer [ 40 , 41 , 42 , 43 , 44 ], anticonvulsant [ 45 ], antidiabetic [ 45 , 46 ], antihypertensive [ 47 ], anti-tuberculosis [ 48 , 49 ], antimalarial [ 50 , 51 ] and antioxidant [ 52 , 53 ] activities.…”

Drug repurposing and human parasitic protozoan diseases

“…In 2006, two screens were carried out using laboratory lines of P. falciparum , yielding numerous hits including the antihistamine astemizole which was also shown to have some activity in vivo in mouse models of malaria ( Chong et al, 2006 ). This compound has since been shown to also have activity against Plasmodium liver stages ( Derbyshire et al, 2012 ) and is being pursued as a starting point for new antimalarial compounds ( Roman et al, 2013 ). Recently, Yuan et al (2011) screened a panel of 61 P. falciparum lines with different drug sensitivities against the NIH Chemical Genomics Center Pharmaceutical Collection which contains 2816 compounds registered or approved for human or animal use ( Huang et al, 2011 ).…”

Synthesis of Benzimidazoles via Domino Intra and Intermolecular C‐N Cross‐Coupling Reaction

“…Benzimidazoles and 2‐aminobenzimidazoles are very powerful compounds because of their applications in therapeutic and biological sciences (Figure ) . These compounds were used as neuropeptide YY1 receptor antagonist, N ‐methyl‐D‐aspartate (NMDA) antagonist, factor Xa(FXa) inhibitor, poly(ADP‐ribose)polymerase (PARP) inhibitor and non‐peptide thrombin inhibitor .…”