Synthesis of sulfonamide, amide and amine hybrid pharmacophore, an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis

Ahmed, Atteeque; Channar, Pervaiz Ali; Saeed, Aamer; Kalesse, Markus; Kazi, Mehar Ali; Larik, Fayaz Ali; Abbas, Qamar; Hassan, Mubashir; Raza, Hussain

doi:10.1016/j.bioorg.2019.01.060

Cited by 12 publications

(8 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Coumarin derivatives ( 2H ‐chromen‐2‐one derivatives) can be accessed by a number of reported syntheses (Chimenti et al, 2009; He et al, 2014; Yang et al, 2019). Herein, coumarin ethyl ester was synthesized according to the route depicted in Scheme 1 (Ahmed et al, 2019; Sağlık et al, 2019). Commercially available 2,4‐dihydroxybenzaldehyde ( 1a ) was reacted with diethyl malonate in the presence of piperidine to afford ethyl 7‐hydroxy‐2‐oxo‐2 H ‐chromene‐3‐carboxylate ( 2a ).…”

Section: Resultsmentioning

confidence: 99%

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Huwaimel

Jonnalagadda

et al. 2023

Drug Development Research

View full text Add to dashboard Cite

Inhibition of specific carbonic anhydrase (CA) enzymes is a validated strategy for the development of agents to target cancer. The CA isoforms IX and XII are overexpressed in various human solid tumors wherein they play a critical role in regulating extracellular tumor acidification, proliferation, and progression. A series of novel sulfonamides based on the coumarin scaffold were designed, synthesized and characterized as potent and selective CA inhibitors. Selected compounds show significant activity and selectivity over CA I and CA II to target the tumor‐associated CA IX and CA XII with high inhibition activity at the single digit nanomolar level. Twelve compounds were identified to be more potent compared with acetazolamide (AAZ) control to inhibit CA IX while one was also more potent than AAZ to inhibit CA XII. Compound 18f (Ki's = 955 nM, 515 nM, 21 nM and 5 nM for CA's I, II, IX, and XII, respectively) is highlighted as a novel CA IX and XII inhibitor for further development.

show abstract

Section: Resultsmentioning

confidence: 99%

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Huwaimel

Jonnalagadda

et al. 2023

Drug Development Research

View full text Add to dashboard Cite

show abstract

“…As mentioned previously, the inhibition of carbonic anhydrase was investigated with adjustments [ 36 , 37 ]. The method relies on the fact that carbonic anhydrase hydrolyzes p-nitrophenyl acetate into yellow-colored p-nitrophenol, which is then quantified spectrophotometrically.…”

Section: Materials and Methodologymentioning

confidence: 99%

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

et al. 2022

Self Cite

View full text Add to dashboard Cite

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of −6.12, −6.99, and −6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

show abstract

“…Carbonic anhydrase inhibition assay . Carbonic anhydrase inhibition was measured as described previously with some modifications [53–55]. The method is based on the principle that p ‐nitrophenyl acetate is hydrolyzed by carbonic anhydrase to form yellow colored p ‐nitrophenol, which was measured spectrophotometrically.…”

Section: Methodsmentioning

confidence: 99%

Convergent synthesis of carbonic anhydrase inhibiting bi‐heterocyclic benzamides: Structure–activity relationship and mechanistic explorations through enzyme inhibition, kinetics, and computational studies

Khan

Abbasi

Aziz-Ur-Rehman

et al. 2021

Journal of Heterocyclic Chem

Self Cite

View full text Add to dashboard Cite

By using a convergent methodology, a novel series of N‐arylated 4‐yl‐benzamides containing a bi‐heterocyclic thiazole–triazole core was synthesized, and the structures of these hybrid molecules, 9a–k, were corroborated through spectral analyses. The in vitro studies of these multifunctional molecules demonstrated their potent carbonic anhydrase inhibition relative to the standard used. The kinetics mechanism was exposed by Lineweaver–Burk plots, which revealed that 9j inhibited carbonic anhydrase non‐competitively by forming an enzyme‐inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 1.2 μM. The computational study was also persuasive with the experimental results, and these molecules disclosed good results of all scoring functions and interactions, which suggested a good binding to carbonic anhydrase. So, it was predicted from the inferred results that these molecules might be considered as promising medicinal scaffolds for various diseases related to the uncontrolled production of this enzyme.

show abstract

Synthesis of sulfonamide, amide and amine hybrid pharmacophore, an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis

Cited by 12 publications

References 36 publications

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Selective carbonic anhydrase IX and XII inhibitors based around a functionalized coumarin scaffold

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

Convergent synthesis of carbonic anhydrase inhibiting bi‐heterocyclic benzamides: Structure–activity relationship and mechanistic explorations through enzyme inhibition, kinetics, and computational studies

Contact Info

Product

Resources

About