Synthesis And Transmembrane Anion Transport Activities Of Benzimidazolyl-based Small-molecule Compounds

Transport of anions across phospholipid bilayers relies on the channel proteins that are embedded in the membranes.Defects in anion-transport proteins may lead to a number of diseases known as channelopathies.It is of particular importance to identify a class of compounds that can restore the functionality of impaired channel proteins.Anion transporters can be divided into two types,natural products and synthetic small-molecule organic compounds.In recent years,a variety of small-molecule organic compounds based on cholic acid,squaramides,polyamides,calix[4]arene,(thio)urea and others,have been reported to exhibit promising anionophoric activities.Benzimidazoles,because of their low molecular weights,ready availability,biocompatibility and ability to form complexes with anions through hydrogen-bonding interaction,are an attractive class of molecular scaffolds for the creation of anion transporters.However,benzimidazolyl-based compounds reported to date exhibit low transmembrane anion transport activities.With the aim to create highly potent small-molecule anion transporters,in the thesis two series of benzimidazolyl-based compounds were designed and synthesized,and their anion transport activities were investigated in details.The first series is 1,3-bis(benzimidazol-2-yl)benzene 1 and its analogues,including 1,3-bis(N-methylbenzimidazol-2-yl)benzene 2,1,4-bis(benzimidazol-2-yl)benzene 3,1,2-bis(benzimidazol-2-yl)benzene 4 and 2-phenylbenzimidazole 5.Compounds 1 and 3-5 were synthesized from the condensation of o-phenylene-diamine with isophthalic acid,phthalic acid,terephthalic acid and benzoic acid,respectively,whereas compound 2 was prepared from the N-methylation of compound 1.The second series is compounds 6-11,in which compounds 6-10 have electron-deficient substituents,whereas compound 11 bears electron-efficient methyl groups.Compounds 6-11 were synthesized from the condensation of isophthalic acid or isophthalaldehyde with o-phenylenediamine having the corresponding substituents.Compounds 1-11 were fully characterized on the basis of ESI-MS,HR-ESI-MS,1H NMR and 13C NMR data.The anion transport properties of compounds 1-11 across the liposomal membranes derived from egg-yolk L-a-phosphatidylcholine(EYPC),were assessed by means of pyranine and lucigenin assays.The results show that compounds 1 and 6-11 exhibits potent anionophoric activity through a process of anion exchange with a minor level of proton/anion symport.However,compounds 2-5 are almost inactive under the assay conditions.In addition,compounds 1 and 6-11 act as mobile carriers.For the second series,compounds 6-10 exhibit much higher transmembrane anion transport activities than compound 11.In particular,compound 10 bearing nitro substituents at the 4-positions of the benzimidazolyl subunits,is 789-fold more active than compound 1.Preliminary study on the structure-activity relationship suggests that the benzimidazolyl-NH fragments are essential for the anion transport activity,and the relative position and the number of benzimidazolyl groups on the central phenyl scaffold play a crucial role in the anion transport process.In addition,introduction of strong electron-withdrawing groups onto the benzimidazolyl subunits is favorable to the anion transport activity.These preliminary structure-activity relationships may provide useful guidance for future rational design of benzimidazolyl-based potent anion transporters.