title: Inhibition studies of quinazoline-sulfonamide derivatives against the γ-CA (PgiCA) from the pathogenic bacterium, Porphyromonas gingivalis.
abstract: Carbonic anhydrases (CAs, EC 4.2.1.1) began to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria CAs are essential for the life cycle of the organism. The presence of CAs in pathogenic bacteria allows the development of anti-infectives with a new mechanism of action, less explored to date. Here, novel quinazoline derivatives crowned with sulfonamide functionality at position-2 were tested for their ability to inhibit the bacterial γ-CA (PgiCA), identified in the genome of Porphyromonas gingivalis. Six compounds were highly effective, nanomolar inhibitors of the pathogenic enzyme γ-PgCA. Three of them were also highly effective sub-nanomolar inhibitors of the cytosolic human isoform II (hCAII). The best γ-PgCA inhibitor was compound 8c, with a K(I) of 3.53 nM and selectivity ratio of 24.5 and 24.8 against hCA I and hCA II, respectively. Many of these new compounds showed a high selectivity for bacterial enzyme respect to the mammalian CA isoforms (hCAI and hCAII). These results suggest that sulfonamides with quinazoline scaffold could be considered as suitable candidates for further derivatization to better understand the role of bacterial CAs in pathogenesis.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University , Alkharj , Saudi Arabia .
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Alafeefy
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.forename: Abdul-Malek S
authors.initials: AM
authors.lastname: Al-Tamimi
authors.forename: Sonia
authors.initials: S
authors.lastname: Del Prete
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
mesh_terms: D000595:Amino Acid Sequence; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010802:Phylogeny; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000201:enzymology; D011799:Quinazolines / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D011799:Quinazolines; D013449:Sulfonamides; D002256:Carbonic Anhydrases
keywords: Carbonic anhydrase; Porphyromonas gingivalis; periodontitis; quinazoline; sulfonamide