RESUMEN
Carbonic anhydrases (CAs) continue to represent a relevant pharmaceutical target. The need of selective inhibitors and the involvement of these metalloenzymes in many multifaceted diseases boost the search for new ligands able to distinguish among the different CA isoforms, and for multifunctional systems simultaneously able to inhibit CAs and to interfere with other pathological events by interacting with additional targets. In this work, we successfully explored the possibility of preparing new CAs ligands by combining calixarenes with benzensulfonamide units. Inhibition tests towards three human CA isoforms evidenced, for some of the ligands, Ki values in the nanomolar range and promising selectivity. X-ray and molecular modeling studies provided information on the mode of binding of these calixarene derivatives. Thanks to the encouraging results and the structural features typical of the calixarene scaffold, it is then possible to plan for the future the design of multifunctional inhibitors for this class of widely spread enzymes.
Asunto(s)
Calixarenos , Anhidrasas Carbónicas , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Humanos , Ligandos , Relación Estructura-Actividad , SulfonamidasRESUMEN
A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-ß and VchCA-γ) and Burkholderia pseudomallei (BpsCA-ß and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.
Asunto(s)
Proteínas Bacterianas/metabolismo , Burkholderia pseudomallei/enzimología , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/metabolismo , Sulfonamidas/química , Tiadiazinas/química , Vibrio cholerae/enzimología , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/metabolismo , Anhidrasas Carbónicas/química , Diseño de Fármacos , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Cinética , Relación Estructura-ActividadRESUMEN
BACKGROUND: Design of isoform-specific inhibitors is a major challenge in the new therapeutic agents development. METHODS: The article describes the development of a robust selectivity for CA XII QSAR and 3DQSAR models of 40 benzenesulfonamide derivatives bearing pyrimidine moieties using PHASE module of Schrödinger for 3D-QSAR or E-DRAGON and R software for 2D-QSAR. Two QSAR protocols were explored: traditional (affinity) and selectivity (affinity ratio) based. RESULTS: A total of 25 2D and 3D-QSAR models were developed using a training set of 30 compounds using the two protocols for 6 CA isoforms. A new ad hoc descriptor T(OH..Cl) was created targeting CA XII affinity. Satisfactory results were obtained in terms of model quality expressed statistically as F, R2 and R2ADJ. Developed models were analyzed using different statistical validation techniques, both by using the Leave One Out (LOO) criterion, and by applying a model on a test set. The Applicability Domains of the 2D-QSAR models were determined. Two PHASE (affinity and selectivity) 3D-QSAR models were rationalized by manual docking of the ligands into the X-ray crystal structures. The affinity and selectivity based protocols were compared. CONCLUSION: This study provides insights for designing sulfonamide compounds with a better isoform selectivity.