Abstract
A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC500.84 ± 0.12 μM among all other derivatives and is also more active than standard acetazolamide (IC500.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with Ki value 8.6 μM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.
Highlights
Carbonic anhydrase (CA) (EC#: 4.2.1.1) is a metal group containing enzymes that hydrate CO2 to bicarbonate ions and vice versa [1]
They are further categorized as α-CAs and are observed primarily in algae, plants, and vertebrates; β-CAs are expressed in bacteria, fungi, and algae; γ-carbonic anhydrase appears in bacteria and archaea [2]
The excellent activity was shown by compound 3c with IC500:84 ± 0 s:12 μM value better than the standard acetazolamide (IC500:99 ± 0:04 μM)
Summary
Carbonic anhydrase (CA) (EC#: 4.2.1.1) is a metal group containing enzymes that hydrate CO2 to bicarbonate ions and vice versa [1]. Various CA isoforms are classified by their structures. Based upon their hosts, they are further categorized as α-CAs and are observed primarily in algae, plants, and vertebrates; β-CAs are expressed in bacteria, fungi, and algae; γ-carbonic anhydrase appears in bacteria and archaea [2]. Two minor isoforms of CA, δ and ζ, are primarily expressed in marine diatoms and η in protozoans, respectively [3]. For their catalytic domains, crystal structures of all isoforms were studied and submitted to the Protein Data Bank (PDB) [4] Crystal structures of all isoforms were studied and submitted to the Protein Data Bank (PDB) [4].
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