2018
DOI: 10.1002/slct.201702562
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Synthesis, Biological Activity and Structure‐Activity Relationship of Novel Diphenylurea Derivatives Containing Tetrahydroquinoline as Carbonic Anhydrase I and II Inhibitors

Abstract: A series of novel tetrahydroquinoline derivatives containing urea moiety was synthesized and their in vitro inhibitory effects on the human carbonic anhydrase isoenzymes (hCA−I and hCA‐II) were evaluated by using the CO2 hydration method. All the synthesized compounds exhibited inhibitory activity against both hCA I and hCA II with 1‐(4‐fluorophenyl)‐3‐(4‐(4‐p‐tolyl‐5,6,7,8‐tetrahydroquinolin‐2‐yl)phenyl)urea (7 k, IC50 value of 5.28 μM and 5.51 μM, against hCA I and hCA II, respectively) as the strongest inhi… Show more

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Cited by 12 publications
(7 citation statements)
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References 70 publications
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“…Using quantum chemical calculations to estimate the parameters related to molecules is an excellent technique for learning about the activities of a molecule even for a reaction path; E HOMO , E L UMO , Δ E (HOMO–LUMO energy difference), hardness, global softness, electronegativity, chemical potential, global electrophilicity, nucleophilicity, ionization energy, dipole moment, and electron affinity, such quantum chemical parameters that can be taken into account for the biological potential of any molecule 67 . On the other hand, carbonic anhydrase inhibitors (CAIs) can inhibit the enzyme by three main mechanisms: (i) directly coordinating with active zinc site, (ii) by anchoring to the Zn(II)‐bound solvent molecule, and (iii) occlusion of the entrance to the active site cavity 68 . Especially, hardness, nucleophilicity, and dipole moment are crucial for these mechanisms.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Using quantum chemical calculations to estimate the parameters related to molecules is an excellent technique for learning about the activities of a molecule even for a reaction path; E HOMO , E L UMO , Δ E (HOMO–LUMO energy difference), hardness, global softness, electronegativity, chemical potential, global electrophilicity, nucleophilicity, ionization energy, dipole moment, and electron affinity, such quantum chemical parameters that can be taken into account for the biological potential of any molecule 67 . On the other hand, carbonic anhydrase inhibitors (CAIs) can inhibit the enzyme by three main mechanisms: (i) directly coordinating with active zinc site, (ii) by anchoring to the Zn(II)‐bound solvent molecule, and (iii) occlusion of the entrance to the active site cavity 68 . Especially, hardness, nucleophilicity, and dipole moment are crucial for these mechanisms.…”
Section: Resultsmentioning
confidence: 99%
“…67 On the other hand, carbonic anhydrase inhibitors (CAIs) can inhibit the enzyme by three main mechanisms: (i) directly coordinating with active zinc site, (ii) by anchoring to the Zn(II)-bound solvent molecule, and (iii) occlusion of the entrance to the active site cavity. 68 Especially, hardness, nucleophilicity, and dipole moment are crucial for these mechanisms. In this context, chemical hardness defines the rigidity of a molecule that affects inclusion of molecule to active site of an enzyme.…”
Section: In Silico Studiesmentioning
confidence: 99%
“…[ 33 ] Compounds 4 and 5 were then reacted with benzaldehyde derivatives ( 6a – e ) in a basic medium to synthesize phenylurea‐substituted chalcones derivatives ( 7a – e and 8a – e ). [ 33–36 ] At the last stage of the study, the synthesis of cyanopyridine derivatives ( 10a – e and 11a – e ) containing the phenylurea unit, which are the resultant target compounds, by the reaction of the phenylurea‐substituted chalcone derivatives ( 7a – e and 8a – e ) with malononitrile was carried out (Scheme 1 and Table 1).…”
Section: Resultsmentioning
confidence: 99%
“…Acetazolamide (AAZ) is one of the best-known CAIs and also used as a standard in CA assays [27]. Whereas complexes and 2 showed much weaker inhibitory activity against hCA I and hCA II than AAZ (Ki of 250 nM and 12.1 nM against hCA I and hCA II, respectively) [28,29],they exhibited higher hCA I and II inhibitory activity than some synthesized compounds (Ki or IC50 values ranging between 75 µM and 620 µM against hCA I, between 126 µM and 427 µM against hCA II) reported as CAIs in the literature [30][31][32][33]. The sulphonamides (known as strong CAIs) bind in the deprotonated form to the catalytically critical Zn(II) ion in the enzyme active site [34,35], also contributing in extensive hydrogen bond and van der Waals interactions with amino acid residues of the enzyme active site, as reported in X-ray crystallographic studies of enzyme-inhibitor complexes [36].…”
Section: Methodsmentioning
confidence: 99%