Abstract
A series of 1,2,3-triazole-linked triazino[5,6-b]indole-benzene sulfonamide hybrids (6a–6o) was synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against the human (h) isoforms hCA I, II, XIII (cytosolic isoforms), and hCA IX (transmembrane tumor-associated isoform). The results revealed that the compounds 6a–6o exhibited Ki values in the low to medium nanomolar range against hCA II and hCA IX (Kis ranging from 7.7 nM to 41.3 nM) and higher Ki values against hCA I and hCA XIII. Compound 6i showed potent inhibition of hCA II (Ki = 7.7nM), being more effective compared to the standard inhibitor acetazolamide (AAZ) (Ki = 12.1 nM). Compounds 6b and 6d showed moderate activity against hCA XIII (Ki = 69.8 and 65.8 nM). Hence, compound 6i could be consider as potential lead candidate for the design of potent and selective hCA II inhibitors.
Highlights
Carbonic anhydrases (CAs, EC 4.2.1.1) are omnipresent metalloenzymes that they play a pivotal catalytic role in the hydration of carbon dioxide to bicarbonate and protons by means of a ping pong mechanism, which is a slow process under non-catalytic conditions [1,2,3,4].CO2 + H2 O ⇔ HCO3 − + H +These enzymes are encoded by eight genetically unrelated gene families, namely, α, β, γ, δ, ζ, η, θ, and the recently reported ι class [5]
The α family is predominantly present in mammals, and 16 isoforms have been reported with different catalytic activity, subcellular localization, and tissue distribution [1,2,3,4]
Owingto to development of novel carbonic anhydrase inhibitors with betterselectivity, isoform our group designed some novel hybrids in which the triazino[5,6-b]indole tail was conjugated selectivity, our group designed some novel hybrids in which the triazino[5,6-b]indole tail wasto benzene sulfonamide viasulfonamide a 1,2,3-triazole
Summary
Carbonic anhydrases (CAs, EC 4.2.1.1) are omnipresent metalloenzymes that they play a pivotal catalytic role in the hydration of carbon dioxide to bicarbonate and protons by means of a ping pong mechanism, which is a slow process under non-catalytic conditions [1,2,3,4]. The sulfonamide group is considered as main zinc-binding group for the design of anhydrase inhibitors. The main drawback of all expressed in tumor cells, and their inhibition results in anti-metastatic effects [13,14,15] These drugs the is the lackdrawback of selectivity, resultsisin serious effects. Owingto to development of novel carbonic anhydrase inhibitors with betterselectivity, isoform our group designed some novel hybrids in which the triazino[5,6-b]indole tail was conjugated selectivity, our group designed some novel hybrids in which the triazino[5,6-b]indole tail wasto benzene sulfonamide viasulfonamide a 1,2,3-triazole. 1,2,4-triazine in in order withbetter better interactions in the enzymatic site and the second one was to incorporate different N-alkyl substituents in the indole tail in a systematic fashion to define optimal length (methyl, ethyl, propyl), bulkiness (isopropyl) and un-saturation (allyl), which would confer the best CA inhibitory activity.
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