Development of a Library of Thiophene‐Based Drug‐Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity

Abstract

The anion-bindinga nd transport properties of an extensive library of thiophene-based molecules are reported. Seventeen bis-urea positional isomers, with different binding conformationsa nd lipophilicities, have been synthesized by appending a-o rb-thiopheneo ra-, b-, or g-benzo[b]thiophene moieties to an ortho-phenylenediamine central core, yielding six subsets of positional isomers. Through 1 HNMR, X-ray crystallography, molecular modelling,a nd anion efflux studies, it is demonstrated that the most active transporters adopt ap re-organized binding conformation capable of pro-moting the recognition of chloride, using urea and CÀH bindingg roups in ac ooperative fashion.A dditional large unilamellar vesicle-based assays, carriedo ut under electroneutral and electrogenic conditions, together with N-methyld-glucamine chloride assays,h ave indicated that anion efflux occurs mainly through an H + /Cl À symportm echanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on acystic fibrosis cell line.

Binding and Transport Properties of a Benzo[b]thiophene‐Based Mono‐(thio)urea Library

“…The 1 H NMR binding studies (vide supra) showed that the α-, βand γ-benzo[b]thiophene (thio)urea motifs recognize chloride thorough the binding modes presented in Scheme 3, in agreement with the experimental and theoretical findings previously observed for chloride complexes of benzo[b]thiophene-based bis-ureas. [6] Therefore, the geometry of the chloride complexes 1-24 were computed for a single binding scenario, with the receptors adopting the putative binding conformations sketched in Scheme 1 and Scheme 2.…”

“…À S δÀ bond, in agreement with the V s distribution of the isolated benzo[b]thiophene. [6] Of note, the The twisting of benzo[b]thiophene binding motifs was measured using the torsion angle ξ at the C α /C β /C γ À N central bond between the urea binding unit and the heteroaromatic fragment, as defined in Scheme 3. The values obtained for the twenty-four optimized geometries (see Table S1) were also cluster analyzed and are listed in Table 2.…”

“…[5] We have recently developed a series of seventeen ophenylenediamine-based bis-urea molecules decorated with thiophene or benzo[b]thiophene motifs. [6] The binding affinity and transmembrane transport ability of these molecules for chloride were comprehensively investigated by experimental and theoretical methods. Remarkably, the spatial binding disposition of the benzo[b]thiophene units dictated the anion binding affinity, with the βand γ-benzo[b]thiophene based receptors having association constant values for chloride that are almost twice as large as the values determined for the αbenzo[b]thiophene isomers.…”

“…Remarkably, the spatial binding disposition of the benzo[b]thiophene units dictated the anion binding affinity, with the βand γ-benzo[b]thiophene based receptors having association constant values for chloride that are almost twice as large as the values determined for the αbenzo[b]thiophene isomers. [6] While the α-benzo[b]thiophene derivatives adopted an extended conformation and recognized chloride only through four hydrogen bonds from the urea binding units, the βand γ-benzo[b]thiophenes derivatives displayed two additional synergetic non-classical CÀ H hydrogen bonds from the nearby benzo[b]thiophene aromatic fragments. This allowed the βand γ-benzo[b]thiophene derivatives to standout in chloride transport across a phospholipid bilayer model (POPC), functioning as very efficient anion carriers.…”

Recent Advances in Bioactive Artificial Ionophores

“…Félix and colleagues reported thiophene appended transporters ( 41 – 43 ) on an ortho ‐phenylenediamine central core which bind with anions by urea and C−H binding groups in a cooperative fashion (Figure 12 B–C). [46] The fluorinated analogues were found to be more active towards anions over non‐fluorinated derivatives and display cytotoxicity against tumour cell lines such as HeLa, MCF‐7 and A549. Recently Manna and co‐workers described conformationally controlled bis(thiourea) derivatives ( 44 a – 44 f ) based on 1,2‐diphenylethylenediamin scaffold.…”