Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i>
In the present study, a series of isatin bis-imidathiazole hybrids was designed and synthesized to develop a new class of heterocyclic compounds with improved antimicrobial activity against pathogens responsible for hospital- and community-acquired infections. A remarkable inhibitory activity agains...
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| Format: | Article |
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MDPI AG
2024-10-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/13/10/992 |
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| author | Rita Morigi Daniele Esposito Matteo Calvaresi Tainah Dorina Marforio Giovanna Angela Gentilomi Francesca Bonvicini Alessandra Locatelli |
| author_facet | Rita Morigi Daniele Esposito Matteo Calvaresi Tainah Dorina Marforio Giovanna Angela Gentilomi Francesca Bonvicini Alessandra Locatelli |
| author_sort | Rita Morigi |
| collection | DOAJ |
| description | In the present study, a series of isatin bis-imidathiazole hybrids was designed and synthesized to develop a new class of heterocyclic compounds with improved antimicrobial activity against pathogens responsible for hospital- and community-acquired infections. A remarkable inhibitory activity against <i>Staphylococcus aureus</i> was demonstrated for a subset of compounds (range: 13.8–90.1 µM) in the absence of toxicity towards epithelial cells and human red blood cells. The best performing derivative was further investigated to measure its anti-biofilm potential and its effectiveness against methicillin-resistant <i>Staphylococcus aureus</i> strains. A structure–activity relationship study of the synthesized molecules led to the recognition of some important structural requirements for the observed antibacterial activity. Molecular docking followed by molecular dynamics (MD) simulations identified the binding site of the active compound FtsZ, a key protein in bacterial cell division, and the mechanism of action, i.e., the inhibition of its polymerization. The overall results may pave the way for a further rational development of isatin hybrids as FtsZ inhibitors, with a broader spectrum of activity against human pathogens and higher potency. |
| format | Article |
| id | doaj-art-24d750abde8f4e928dcd68fcee3c6937 |
| institution | OA Journals |
| issn | 2079-6382 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj-art-24d750abde8f4e928dcd68fcee3c69372025-08-20T02:11:04ZengMDPI AGAntibiotics2079-63822024-10-01131099210.3390/antibiotics13100992Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i>Rita Morigi0Daniele Esposito1Matteo Calvaresi2Tainah Dorina Marforio3Giovanna Angela Gentilomi4Francesca Bonvicini5Alessandra Locatelli6Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, ItalyDepartment of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, ItalyDepartment of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum-University of Bologna, Via Selmi 2, 40126 Bologna, ItalyDepartment of Chemistry “Giacomo Ciamician”, Alma Mater Studiorum-University of Bologna, Via Selmi 2, 40126 Bologna, ItalyDepartment of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Massarenti 9, 40138 Bologna, ItalyDepartment of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Massarenti 9, 40138 Bologna, ItalyDepartment of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, ItalyIn the present study, a series of isatin bis-imidathiazole hybrids was designed and synthesized to develop a new class of heterocyclic compounds with improved antimicrobial activity against pathogens responsible for hospital- and community-acquired infections. A remarkable inhibitory activity against <i>Staphylococcus aureus</i> was demonstrated for a subset of compounds (range: 13.8–90.1 µM) in the absence of toxicity towards epithelial cells and human red blood cells. The best performing derivative was further investigated to measure its anti-biofilm potential and its effectiveness against methicillin-resistant <i>Staphylococcus aureus</i> strains. A structure–activity relationship study of the synthesized molecules led to the recognition of some important structural requirements for the observed antibacterial activity. Molecular docking followed by molecular dynamics (MD) simulations identified the binding site of the active compound FtsZ, a key protein in bacterial cell division, and the mechanism of action, i.e., the inhibition of its polymerization. The overall results may pave the way for a further rational development of isatin hybrids as FtsZ inhibitors, with a broader spectrum of activity against human pathogens and higher potency.https://www.mdpi.com/2079-6382/13/10/992isatin bis-imidathiazole hybridsantibacterial activityMRSAFtsZ inhibitorsmolecular dynamics simulations |
| spellingShingle | Rita Morigi Daniele Esposito Matteo Calvaresi Tainah Dorina Marforio Giovanna Angela Gentilomi Francesca Bonvicini Alessandra Locatelli Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i> Antibiotics isatin bis-imidathiazole hybrids antibacterial activity MRSA FtsZ inhibitors molecular dynamics simulations |
| title | Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i> |
| title_full | Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i> |
| title_fullStr | Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i> |
| title_full_unstemmed | Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i> |
| title_short | Isatin Bis-Imidathiazole Hybrids Identified as FtsZ Inhibitors with On-Target Activity Against <i>Staphylococcus aureus</i> |
| title_sort | isatin bis imidathiazole hybrids identified as ftsz inhibitors with on target activity against i staphylococcus aureus i |
| topic | isatin bis-imidathiazole hybrids antibacterial activity MRSA FtsZ inhibitors molecular dynamics simulations |
| url | https://www.mdpi.com/2079-6382/13/10/992 |
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