title: N-Heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold with anticancer and anti-infective dual action.
abstract: BACKGROUND
  Pharmacological effects of biologically active "small molecules" can be improved by their targeted modification, which affects drug delivery and interaction with tumor cells and microorganisms. We aimed to evaluate anticancer and antimicrobial activity of lipid-like choline derivatives modified via simultaneous introduction of tetrahydro(iso)quinoline based pharmacophore system at nitrogen atom and long chain alkyl substituent at oxygen atom.
  
  
  METHODS
  Target compounds were synthesized under phase-transfer catalysis conditions followed by quaternization, and evaluated for cytotoxicity and NO-generation ability on HT-1080 and MG-22A tumor cell lines and NIH 3T3 normal mouse fibroblasts, and screened for antimicrobial activity against gram-positive (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis) and fungi (Candida albicans and Aspergillus niger). Inhibitory action of active compounds towards E. coli DNA gyrase was investigated.
  
  
  RESULTS
  Target compounds exhibit high selective cytotoxicity (LC50<1μg/mL) and NO-induction ability, and reveal strong antimicrobial activity with MIC and MBC/MFC values of 0.5-32μg/mL, predominantly vs. gram-positive bacteria and fungi. Tested substances displayed inhibitory effect towards E. coli DNA gyrase, though less than ciprofloxacin. Tetrahydroisoquinoline derivatives and compounds possessing substituents with chain length of 10 and 11 carbon atoms have highest indices of activities.
  
  
  CONCLUSIONS
  Lipid-like N-heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold, possessing very high cytotoxicity with attendant strong antimicrobial activity are the leads for developing effective dual action therapeutics.
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia. Electronic address: aez@osi.lv.
authors.forename: Alla
authors.initials: A
authors.lastname: Zablotskaya
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Izolda
authors.initials: I
authors.lastname: Segal
authors.affiliation: Aristotle University of Thessaloniki, School of Pharmacy, Thessaloniki, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Geronikaki
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: Irina
authors.initials: I
authors.lastname: Shestakova
authors.affiliation: University of Latvia, Department of Biology, Riga, Latvia.
authors.forename: Vizma
authors.initials: V
authors.lastname: Nikolajeva
authors.affiliation: University of Latvia, Department of Biology, Riga, Latvia.
authors.forename: Galina
authors.initials: G
authors.lastname: Makarenkova
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002794:Choline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D005658:Fungi / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D011804:Quinolines; D002794:Choline
keywords: Antibacterial activity; Antifungal activity; Antitumor activity; Gyrase inhibitory properties; Tetrahydro(iso)quinoline