Development of a library of thiophene-based drug-like LEGO molecules: evaluation of their anion binding, transport properties and cytotoxicity

Abstract

The anion binding and transport properties of an extensive library of thiophene-based molecules are reported. Seventeen bis-urea positional isomers, with different binding conformations and lipophilicities, were synthetized by the appendage of α-, β-thiophene or α-, β-, γ-benzo[b]thiophene motifs to the ortho-phenylenediamine central core, yielding six subsets of positional isomers. Through 1H NMR, X-ray crystallography, molecular modelling and anion efflux studies, it was demonstrated that the most active transporters display a pre-organised binding conformation able to promote the recognition of chloride using urea and C-H binding groups in a cooperative fashion. Additional LUV based assays, carried out under electroneutral and electrogenic conditions, together with NMDG-Cl assays, indicate that anion efflux occurs mainly through H+/Cl– symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumour cell lines while having no effects on a cystic fibrosis cell line.