More effective dithiocarbamate derivatives inhibiting carbonic anhydrases, generated by QSAR and computational design

Dithiocarbamates with potent inhibitory activity against theSaccharomyces cerevisiaeβ-carbonic anhydrase

“…The choice of these scaffolds was motivated by the fact that the structure-activity relationship (SAR) for the inhibition of CAs with the DTCs reported earlier 7,8 was primarily influenced by the organic scaffold of the inhibitor. In fact, important differences of activity were observed between primary and secondary DTCs and between aliphatic or aromatic/ heterocyclic derivatives, respectively [40][41][42][43][44] . Here we investigated compounds belonging to these DTCs types, with a variety of substitution patterns, based on several scaffolds mentioned earlier (Table 1) among which primary, aliphatic aminoalkyl-or hydroxyalkyl derivatives (1b-4b); primary, bicyclic, bulky DTCs (5b-7b), with various stereochemistries; secondary, piperidine, morpholine and piperazine-based DTCs, of types 8b-19b, for which the lead compound was the morpholine-DTC (compound C) reported earlier 40 .…”

“…In the present article, we extended the series of DTCs investigated earlier [40][41][42][43][44] , including both primary as well as secondary derivatives, which were obtained in such a way as to explore novel chemical space. The starting amines (1a-21a) used to synthesize DTCs 1b-21b reported here (Scheme 1) included N,N-dimethylaminoethylenediamine 1a, aminoalcohols with three to five carbon atoms in their molecule 2a-4a, the bicyclic quinuclidine-3-amine (both the racemate as well as the R-and S-enantiomeric DTCs 5b-7b incorporating this scaffold were obtained), piperidine 8a and several of its derivatives with hydroxyl-, carboxy-, acetamido-and boc-amido functionalities in various positions of the heterocyclic ring, of types 9a-16a; morpholine and piperazine derivatives 17a-19a, as well as phenethylamine 20a and its sulfamoylated derivative, 4-aminoethylbenzenesulfonamide 21a, a well know CAI which binds to the enzyme through the sulfamoyl moiety 1,3 (Scheme 1).…”

“…As seen from Figure 1, the binding mode of the new ZBG present in these compounds was identical to that of TTC, with one sulfur coordinated to the metal ion, but the organic scaffold present in the DTC was observed to make extensive contacts with many amino acid residues from the active site. This explains the wide range of inhibitory power of these derivatives, from the subnanomolar to the micromolar range, for the entire series of around 30 DTC reported so far [40][41][42][43][44] . Interestingly, these compounds are highly water soluble (being salts), and the DTC C was also effective in vivo as an antiglaucoma agent when administered topically directly to the eye of hypertensive rabbits, a widely used animal model of this disease 41 .…”

“…The interest in CAIs is mainly motivated by their pharmacological properties and clinical use as diuretics, antiglaucoma, antiobesity or antiepileptic agents, as well as anticancer agents/diagnostic tools [1][2][3][29][30][31][32][33][34][35][36][37][38][39] . Among the new chemotypes with CA inhibitory properties ultimately reported, the dithiocarbamates (DTCs) are undoubtedly among the most interesting ones [40][41][42][43][44] . These compounds have been rationally discovered as CAIs after our report of trithiocarbonate (CS 2À 3 , TTC), an inorganic anion similar to carbonate, as an interesting (milli-micromolar) CAI 45 .…”

“…Thus, the CS À 2 moiety present in TTC was detected as a new zinc-binding group (ZBG) for CA inhibition. As DTCs incorporate this ZBG, a first series of such compounds was prepared and evaluated for their inhibitory activity against several mammalian, fungal and bacterial CAs by this group [40][41][42][43][44] . Several low nanomolar and subnanomolar CAIs were thus detected against all these enzymes.…”