Development of a library of thiophene‐based drug‐like Lego molecules: Evaluation of their anion binding, transport properties, and cytotoxicity

Vieira, Paulo, Miranda, Margarida Q., Marques, Igor, Carvalho, Sílvia, Chen, Li‐jun, Howe, Ethan N. W., Zhen, Carl, Leung, Claudia Y., Spooner, Michael J., Morgado, Bárbara, Cruz E Silva, Odete A. B., Moiteiro, Cristina, Gale, Philip A. and Félix, Vítor (2020) Development of a library of thiophene‐based drug‐like Lego molecules: Evaluation of their anion binding, transport properties, and cytotoxicity. Chemistry - A European Journal, 26 (4), 888-899. (doi:10.1002/chem.201904255).

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, have been synthesized by appending α‐ or β‐thiophene or α‐, β‐, or γ‐benzo[b]thiophene moieties to an ortho‐phenylenediamine central core, yielding six subsets of positional isomers. Through 1H NMR, X‐ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre‐organized binding conformation capable of promoting the recognition of chloride, using urea and C−H binding groups in a cooperative fashion. Additional large unilamellar vesicle‐based assays, carried out under electroneutral and electrogenic conditions, together with N‐methyl‐d‐glucamine chloride assays, have indicated that anion efflux occurs mainly through an H+/Cl− symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.

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Contributors

Author: Philip A. Gale

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