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Journal of Enzyme Inhibition and Medicinal Chemistry Volume 35, 2020 - Issue 1
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Brief Report

Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation

Paolo Guglielmia Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, ItalyORCID Iconhttps://orcid.org/0000-0002-5452-8869View further author information
ORCID Icon,
Giulia Rotondia Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, ItalyView further author information
,
Daniela Seccia Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, ItalyORCID Iconhttps://orcid.org/0000-0001-8115-026XView further author information
ORCID Icon,
Andrea Angelib Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Italy;c Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, Iasi, RomaniaORCID Iconhttps://orcid.org/0000-0002-1470-7192View further author information
ORCID Icon,
Paola Chimentia Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, Rome, ItalyView further author information
,
Alessio Nocentinib Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Italy;d Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR University of Florence, Sesto FiorentinoItalyORCID Iconhttps://orcid.org/0000-0003-3342-702XView further author information
ORCID Icon,
Alessandro Bonardib Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Italy;d Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR University of Florence, Sesto FiorentinoItalyView further author information
,
Paola Gratterib Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Italy;d Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR University of Florence, Sesto FiorentinoItalyView further author information
,
Simone Carradorie Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Chieti, ItalyCorrespondence[email protected] [email protected]
ORCID Iconhttps://orcid.org/0000-0002-8698-9440View further author information
ORCID Icon &
Claudiu T. Supuranb Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, ItalyCorrespondence[email protected] [email protected]
ORCID Iconhttps://orcid.org/0000-0003-4262-0323View further author information
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Pages 1891-1905 | Received 24 Aug 2020, Accepted 18 Sep 2020, Published online: 02 Oct 2020

Figures & data

Figure 1. (a) The first design strategy proposed in this paper; (b) design and retrosynthetic approach for novel hCAs potential inhibitors.

Figure 1. (a) The first design strategy proposed in this paper; (b) design and retrosynthetic approach for novel hCAs potential inhibitors.

Figure 2. The third approach for the saccharin scaffold development.

Figure 2. The third approach for the saccharin scaffold development.

Figure 3. The first and third approaches applied on the acesulfame scaffold.

Figure 3. The first and third approaches applied on the acesulfame scaffold.

Scheme 1. Synthetic procedure for derivatives 1–4 and 50–52.

Scheme 1. Synthetic procedure for derivatives 1–4 and 50–52.

Scheme 2. Synthetic procedure for derivatives 5–16, 17–28 and 29–40.

Scheme 2. Synthetic procedure for derivatives 5–16, 17–28 and 29–40.

Scheme 3. Synthetic procedure for derivatives 41–49.

Scheme 3. Synthetic procedure for derivatives 41–49.

Scheme 4. Synthetic procedure for derivatives 53–60.

Scheme 4. Synthetic procedure for derivatives 53–60.

Table 1. Inhibition data of selected human CA isoforms (hCA I, II, IX and XII) with saccharin-based derivatives 1–49 reported here and the standard sulphonamide inhibitor acetazolamide (AAZ) by a stopped flow CO2 hydrase assayCitation49.

Table 2. Inhibition data of selected human CA isoforms (hCA I, II, IX and XII) with acesulfame-based derivatives 50–60 reported here and the standard sulphonamide inhibitor acetazolamide (AAZ) by a stopped flow CO2 hydrase assayCitation49.

Figure 4. Predicted binding mode of compounds 2 and 46 into (A, C) CA IX and (B, D) CA XII active site. H-bonds and π-π stackings are represented as black and blue dashed lines, respectively. Dashed bonds occupancy over the MD simulation is indicated as percentage, among which underlined is the occupancy of the anchorage to the zinc-bound water. Water molecules are shown as red spheres. Amino acids are labelled with one letter symbols: A, Ala; H, His; K, Lys; L, Leu; N, Asn; P, Pro; Q, Gln; S, Ser; T, Thr; V, Val; W, Trp.

Figure 4. Predicted binding mode of compounds 2 and 46 into (A, C) CA IX and (B, D) CA XII active site. H-bonds and π-π stackings are represented as black and blue dashed lines, respectively. Dashed bonds occupancy over the MD simulation is indicated as percentage, among which underlined is the occupancy of the anchorage to the zinc-bound water. Water molecules are shown as red spheres. Amino acids are labelled with one letter symbols: A, Ala; H, His; K, Lys; L, Leu; N, Asn; P, Pro; Q, Gln; S, Ser; T, Thr; V, Val; W, Trp.

Figure 5. Predicted binding mode of compounds 49 and 51 into (A, C) CA IX and (B, D) CA XII active site. H-bonds and π-π stackings are represented as black and blue dashed lines, respectively. Dashed bonds occupancy over the MD simulation is indicated as percentage, among which underlined is the occupancy of the anchorage to the zinc-bound water. Water molecules are shown as red spheres. Amino acids are labelled with one letter symbols: A, Ala; H, His; K, Lys; L, Leu; N, Asn; P, Pro; Q, Gln; S, Ser; T, Thr; V, Val; W, Trp.

Figure 5. Predicted binding mode of compounds 49 and 51 into (A, C) CA IX and (B, D) CA XII active site. H-bonds and π-π stackings are represented as black and blue dashed lines, respectively. Dashed bonds occupancy over the MD simulation is indicated as percentage, among which underlined is the occupancy of the anchorage to the zinc-bound water. Water molecules are shown as red spheres. Amino acids are labelled with one letter symbols: A, Ala; H, His; K, Lys; L, Leu; N, Asn; P, Pro; Q, Gln; S, Ser; T, Thr; V, Val; W, Trp.
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