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Bioorganometallic derivatives of 4-hydrazino-benzenesulphonamide as carbonic anhydrase inhibitors: synthesis, characterisation and biological evaluation.

ABSTRACT: A series of bio-organometallic-hydrazones of the general formula [{(η⁵-C₅H₄)-C(R)=N-N(H)-C₆H₄-4-SO₂NH₂}]MLn(MLn = Re(CO)₃, Mn(CO)₃, FeCp; R=H, CH₃) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, ¹H and ¹³C NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7-22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (K_Is of 1.9-24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.

SUBMITTER: Brichet J

PROVIDER: S-EPMC7034112 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Bioorganometallic derivatives of 4-hydrazino-benzenesulphonamide as carbonic anhydrase inhibitors: synthesis, characterisation and biological evaluation.

Brichet Jeremie J Arancibia Rodrigo R Berrino Emanuela E Supuran Claudiu T CT

Journal of enzyme inhibition and medicinal chemistry 20201201 1

A series of bio-organometallic-hydrazones of the general formula [{(η5-C5H4)-C(R)=N-N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)3, Mn(CO)3, FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, 1H and 13C NMR, mass spectr ...[more]

PMID: 32037900

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Project description:A series of sulfonamide-derived quinoxaline 1,4-dioxides were synthesized and evaluated as inhibitors of carbonic anhydrases (CA) with antiproliferative potency. Overall, the synthesized compounds demonstrated good inhibitory activity against four CA isoforms. Compound 7g exhibited favorable potency in inhibiting a CA IX isozyme with a K i value of 42.2 nM compared to the reference AAZ (K i = 25.7 nM). Nevertheless, most of the synthesized compounds have their highest activity against CA I and CA II isoforms over CA IX and CA XII. A molecular modeling study was used for an estimation of the binding mode of the selected ligand 7g in the active site of CA IX. The most active compounds (7b, 7f, 7h, and 18) exhibited significant antiproliferative activity against MCF-7, Capan-1, DND-41, HL60, and Z138 cell lines, with IC50 values in low micromolar concentrations. Moreover, derivatives 7a, 7e, and 8g showed similar hypoxic cytotoxic activity and selectivity compared to tirapazamine (TPZ) against adenocarcinoma cells MCF-7. The structure-activity relationships analysis revealed that the presence of a halogen atom or a sulfonamide group as substituents in the phenyl ring of quinoxaline-2-carbonitrile 1,4-dioxides was favorable for overall cytotoxicity against most of the tested cancer cell lines. Additionally, the presence of a carbonitrile fragment in position 2 of the heterocycle also had a positive effect on the antitumor properties of such derivatives against the majority of cell lines. The most potent derivative, 3-trifluoromethylquinoxaline 1,4-dioxide 7h, demonstrated higher or close antiproliferative activity compared to the reference agents, such as doxorubicin, and etoposide, with an IC50 range of 1.3-2.1 μM. Analysis of the obtained results revealed important patterns in the structure-activity relationship. Moreover, these findings highlight the potential of selected lead sulfonamides on the quinoxaline 1,4-dioxide scaffold for further in-depth evaluation and development of chemotherapeutic agents targeting carbonic anhydrases.

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Bioorganometallic derivatives of 4-hydrazino-benzenesulphonamide as carbonic anhydrase inhibitors: synthesis, characterisation and biological evaluation.

Publications

Bioorganometallic derivatives of 4-hydrazino-benzenesulphonamide as carbonic anhydrase inhibitors: synthesis, characterisation and biological evaluation.

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