Synthesis of novel acridine bis-sulfonamides with effective inhibitory activity against the carbonic anhydrase isoforms I, II, IX and XII.
Summary (2 min read)
- Acridines are planar tricyclic aromatic compounds which contain nitrogen in the heterocyclic ring.
- 14 The sulfonamides and their isosteres such as the sulfamates and sulfamides, are established CAIs and are in clinical use for almost Chart 1.
- Some drugs incorporating acridine moieties.
- The large use of CAIs for pharmaceutical applications relies on the wide distribution of the 15 human (h) CA isoforms within different tissues as well as on their implication in many physiological/pathological conditions.
- 13,14 In vivo experiments showed that silencing of hCA IX reduces xenograft tumors to 40% of the volume along with up-regulation response of the gene encoding for hCA XII.
- The general synthetic method, three steps reaction shown in Scheme 1, was used to prepare the nitro acridine derivatives (4a and 4b), novel amino acridine compounds (5a and 5b) and novel acridine bis-sulfonamide compounds (6a–l).
- For the second step, new amino acridine derivatives (5a and b) were synthesized by using excessive reduction reactive—aqueous sodium poly-sulfide—from nitro acridine compounds (4a and 4b) at reflux temperature with high yields (respectively, 87% and 82%).
- For the compounds 6b, 6e, 6h and 6k singlet peaks were observed in between 2.18 and 2.52 ppm belong to protons of the methyl group.
- Standard errors were in the range of ±5–10% of the reported values (data not shown).
- The 13C NMR (APT) spectra of the compounds 5a, 5b and 6a–l displayed 2.09 4.55 6.92 8.91 4.27 4.31 0 1 2 3 4 5 6 7 8 9 10 1 2 3 K I (µ M ) KIs for hC 6a Chart 2.
2.2. Carbonic anhydrase inhibition
- The new compounds reported here and the standard drug acetazolamide were assayed as inhibitors of four cytosolic human isoforms, hCA I, II, IX and XII (Table 1).
- It was observed that increasing of the bulkiness of the tails for the compound series 4a, 4b, and 6a–f (Chart 2) resulted with slight increasing of KI values, that is, decreasing on inhibitory effect, in the range of 0.69–6.92 lM.
- Change in the KI values for 6a–f (red line) and 6g–l (blue line).
- For the dominant cytosolic isoform hCA II, as for isoform CA I, it was observed that the new derivatives were rather ineffective inhibitors, showing a limited range of inhibitory power, with a variation of KI between 0.10 and 0.96 lM.
- The small range of inhibitory power of these compounds against the two transmembrane isoforms may be due to the fact that the variations in the structure are at rather distant parts of the tail from the primary sulfonamide, and the authors hypothesize that these parts of the molecules lay outside the active site, affording thus for less specific interactions with amino acid residues crucial for the binding of inhibitors.
- There are still many important drug design aspect to be addressed for obtaining isoform-selective and more effective sulfonamide CAIs.
- Considering their interest in sulfonamides, herein the authors investigate a new series of acridine bis-sulfonamides which have been obtained by using multicomponent reaction techniques.
- The compounds were characterized by physicochemical methods and tested for their in vitro inhibition activity against the CA isoforms I, II, IX and XII.
- Several compounds showed low micromolar inhibition against the pharmacologically relevant isoforms hCA I, II, IX, and XII.
- The prepared compounds containing both acridine ring and sulfonamide group are thought to be of interest because sulfonamides are used in the treatment of many diseases, possessing antimicrobial, antimalarial, antiglaucoma, and anticancer properties.
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