Design, synthesis and mechanistic study of new benzenesulfonamide derivatives as anticancer and antimicrobial agents <i>via</i> carbonic anhydrase IX inhibition

Nemr, Mohamed T. M.; AboulMagd, Asmaa M.; Hassan, Hossam M.; Hamed, Ahmed A.; Hamed, Mohamed I. A.; El‐Saadi, Mohammed T.

doi:10.1039/d1ra05277b

Cited by 52 publications

(25 citation statements)

References 51 publications

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“…Again, these two derivatives were proven to be the most reactive ones, and this result complements the findings from previous sections. These values were higher by several kJ mol −1 than for AZA, which reproduces the previous docking studies including this native ligand well [17]. This result was expected, as AZA also contains several active positions bearing electronegative nitrogen and sulfur atoms.…”

Section: Conformationssupporting

confidence: 88%

“…The protein-ligand interactions between coumarin-neurotransmitter derivatives and amino acids in the active site of the hCA-IX receptor were examined using molecular docking. This protein was taken as a docking model for the explanation of the antitumor experimental activity in several studies [17,19]. Additionally, this protein was chosen because the selected inhibitors (out of seven million compounds) of hCA-IX in the study by Salmas and co-workers showed structural similarities with the obtained compounds [20].…”

Section: Active Site Confirmation and Molecular Docking Analysismentioning

confidence: 99%

“…This protein is a member of the α-CA family of enzymes associated with the plasma membrane and participates in the acidification of solid tumors. The significant change of pH is a result of the metabolism shift to anaerobic glycolysis [17]. CAs (EC 4.2.1.1) are zinc-containing metalloenzymes that catalyze the reversible hydration of carbon dioxide in a two-step reaction, to yield bicarbonate and protons [18].…”

Section: Introductionmentioning

confidence: 99%

“…The activity of this protein is a sign of tumor hypoxia and presents a prognostic factor in several human cancers. Selective inhibition of this protein is a potential mode of action for new antiproliferative agents [17,19]. An abnormal increase in CA IX expression in chronic hypoxia and during the development of various cancers con-tributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control [20].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Crystallographic, Quantum Chemical, Antitumor, and Molecular Docking/Dynamic Studies of 4-Hydroxycoumarin-Neurotransmitter Derivatives

Dimić

Kaluđerović

Avdović

et al. 2022

IJMS

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In this contribution, four new compounds synthesized from 4-hydroxycoumarin and tyramine/octopamine/norepinephrine/3-methoxytyramine are characterized spectroscopically (IR and NMR), chromatographically (UHPLC-DAD), and structurally at the B3LYP/6-311++G*(d,p) level of theory. The crystal structure of the 4-hydroxycoumarin-octopamine derivative was solved and used as a starting geometry for structural optimization. Along with the previously obtained 4-hydroxycoumarin-dopamine derivative, the intramolecular interactions governing the stability of these compounds were quantified by NBO and QTAIM analyses. Condensed Fukui functions and the HOMO-LUMO gap were calculated and correlated with the number and position of OH groups in the structures. In vitro cytotoxicity experiments were performed to elucidate the possible antitumor activity of the tested substances. For this purpose, four cell lines were selected, namely human colon cancer (HCT-116), human adenocarcinoma (HeLa), human breast cancer (MDA-MB-231), and healthy human lung fibroblast (MRC-5) lines. A significant selectivity towards colorectal carcinoma cells was observed. Molecular docking and molecular dynamics studies with carbonic anhydrase, a prognostic factor in several cancers, complemented the experimental results. The calculated MD binding energies coincided well with the experimental activity, and indicated 4-hydroxycoumarin-dopamine and 4-hydroxycoumarin-3-methoxytyramine as the most active compounds. The ecotoxicology assessment proved that the obtained compounds have a low impact on the daphnia, fish, and green algae population.

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Section: Conformationssupporting

confidence: 88%

Section: Active Site Confirmation and Molecular Docking Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, Crystallographic, Quantum Chemical, Antitumor, and Molecular Docking/Dynamic Studies of 4-Hydroxycoumarin-Neurotransmitter Derivatives

Dimić

Kaluđerović

Avdović

et al. 2022

IJMS

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“…Nowadays, cancer is considered to be the second leading cause of death after cardiovascular diseases [1][2][3]. According to the World Health Organization, around 14 million new cases and 9 million new deaths occur per year [4].…”

Section: Introductionmentioning

confidence: 99%

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

et al. 2021

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A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

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Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

Bendi,

Taruna,

Rajni

et al. 2024

Archiv der Pharmazie

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Nowadays, the scientific community has focused on dealing with different kinds of diseases by exploring the chemistry of various heterocycles as novel drugs. In this connection, medicinal chemists identified carbonic anhydrases (CA) as one of the biologically active targets for curing various diseases. The widespread distribution of these enzymes and the high degree of homology shared by the different isoforms offer substantial challenges to discovering potential drugs. Medicinal and synthetic organic chemists have been continuously involved in developing CA inhibitors. This review explored the chemistry of different heterocycles as CA inhibitors using the last 11 years of published research work. It provides a pathway for young researchers to further explore the chemistry of a variety of synthetic as well as natural heterocycles as CA inhibitors.

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Design, synthesis and mechanistic study of new benzenesulfonamide derivatives as anticancer and antimicrobial agents via carbonic anhydrase IX inhibition

Abstract: New benzenesulfonamide derivatives as anticancer and antimicrobial agents via CA IX inhibition.

Cited by 52 publications

References 51 publications

Synthesis, Crystallographic, Quantum Chemical, Antitumor, and Molecular Docking/Dynamic Studies of 4-Hydroxycoumarin-Neurotransmitter Derivatives

Synthesis, Crystallographic, Quantum Chemical, Antitumor, and Molecular Docking/Dynamic Studies of 4-Hydroxycoumarin-Neurotransmitter Derivatives

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

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