title: Synthesis, Antibacterial Activity, Interaction with Nucleobase and Molecular Docking Studies of 4-Formylbenzoic Acid Based Thiazoles.
abstract: BACKGROUND
  Synthesis, characterization and investigation of antibacterial activity of ten novel Schiff base derivatives of 4-formylbenzoic acid is presented. Their structures were determined using 1H and 13CNMR, EI(+)-MS and elemental analyses. Additionally, DFT calculations of interaction energies in complexes of the novel drugs and DNA bases are carried out.
  
  
  OBJECTIVE
  Design and synthesis of thiazole derivatives with benzoic acid scaffold to obtain compounds with an improved antibacterial activity.
  
  
  METHODS
  The examined compounds were screened in vitro for antibacterial activity using the broth microdilution method. Geometrical parameters of the investigated complexes were optimized within the Density Functional Theory (DFT) approximation using the B3LYP functional and the 6-311G** basis set. The docking simulations were performed using the FlexX docking module.
  
  
  RESULTS
  Among the derivatives, compound 4b showed very strong bacterial activity against staphylococci, MIC 1.95-3.91 µg/ml, micrococci, MIC 0.98 µg/ml, and Bacillus spp., MIC 7.81-15.62 µg/ml. The compounds 4c, 4d, 4e and 4j also showed high bioactivity against staphylococci, MIC 3.91-31.25 µg/ml, and micrococci, MIC 0.98-15.62 µg/ml. Interaction energy values for investigated guanine complexes are about 2 kcal/mol lower than for the corresponding cytosine complexes. Molecular docking studies of all compounds on the active sites of bacterial enzymes indicated gyrase B as possible target.
  
  
  CONCLUSIONS
  To conclude, an efficient and economic method for the synthesis of thiazoles containing benzoic acid moiety has been developed. The results of antibacterial screenings reveal that some obtained compounds show high to very strong antibacterial activity. The DFT calculations showed that interaction of the obtained drugs with guanine is stronger than with cytosine. Molecular docking studies of all compounds on the active sites of bacterial enzymes indicated gyrase B as possible target.
authors.affiliation: Department of Chemical Technology and Pharmaceuticals, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland. krzysztof.laczkowski@cm.umk.pl.
authors.forename: Krzysztof Z
authors.initials: KZ
authors.lastname: Laczkowski
authors.forename: Anna
authors.initials: A
authors.lastname: Biernasiuk
authors.forename: Angelika
authors.initials: A
authors.lastname: Baranowska-Laczkowska
authors.forename: Konrad
authors.initials: K
authors.lastname: Misiura
authors.forename: Anna
authors.initials: A
authors.lastname: Malm
authors.forename: Tomasz
authors.initials: T
authors.lastname: Plech
authors.forename: Agata
authors.initials: A
authors.lastname: Paneth
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry; D000225:Adenine / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003596:Cytosine / Q000737:chemistry; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000737:chemistry; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006147:Guanine / Q000737:chemistry; D062105:Molecular Docking Simulation; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013941:Thymine / Q000737:chemistry; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001565:Benzoates; D013844:Thiazoles; D059005:Topoisomerase II Inhibitors; D006147:Guanine; D003596:Cytosine; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D027101:DNA Topoisomerase IV; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase; D000225:Adenine; D013941:Thymine