Synthesis, biological evaluation and molecular docking studies of novel quinuclidinone derivatives as potential antimicrobial and anticonvulsant agents

• Published in: Medicinal chemistry research 2017-09, Vol.26 (9), p.2088-2104
• Main Authors: Łączkowski, Krzysztof Z., Landowska, Katarzyna, Biernasiuk, Anna, Sałat, Kinga, Furgała, Anna, Plech, Tomasz, Malm, Anna
• Format: Article
• Language: English
• Subjects: Antibiotics; Anticonvulsants; Antiinfectives and antibacterials; Aspartic proteinase; Bacteria; Bactericidal activity; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Chemical synthesis; Deoxyribonucleic acid; Derivatives; DNA; DNA topoisomerase; Enzymes; Fungi; Fungicides; Gram-negative bacteria; Gram-positive bacteria; Microorganisms; Minimum inhibitory concentration; Molecular docking; Motor skill; Original Research; Pharmacology/Toxicology; Pilocarpine; Proteinase; Seizures
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-017-1904-z

Synthesis and investigation of antimicrobial and anticonvulsant activity of eleven novel quinuclidinone-thiazole derivatives are presented. Among the derivatives, compounds 3a – 3f showed a broad-spectrum antibiotic activity against all reference Gram-positive or Gram-negative bacteria and fungi. These compounds exhibited very strong or good bactericidal activity towards Gram-positive bacteria ( Staphylococcus spp., Micrococcus spp. and Bacillus spp.) with MIC = 0.48–15.62 µg/ml. The tested substances 3a – e and 3f were found also to be active against reference Gram-negative bacteria ( Bordetella spp. and rod - shaped bacteria of the family Enterobacteriaceae ) with MIC = 31.25–500 µg/ml. The fungicidal effect of compounds 3a – e was very strong or strong against Candida spp. with MIC = 1.95–31.25 µg/ml. The results of anticonvulsant screening revealed that the compound 3f demonstrated high anticonvulsant activity in electrically-induced seizure models, i.e., MES and 6-Hz tests. It was also effective in pilocarpine-induced model of seizures. Noteworthy, 3f did not impair animals’ motor skills in the rotarod test. Molecular docking studies of all compounds into the active sites of microbial enzymes indicated secreted aspartic proteinase as possible antifungal target and DNA gyrase subunit A as possible antibacterial target.