Andrzej Zięba

Synthesis and in vitro antiproliferative activity of 5-alkyl-12(H)-quino[3,4-b] [1,4]benzothiazinium salts.

A novel method of synthesizing 1,4-thiazine ring has led to the series of 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts. The derivatives containing a butyl or decyl substituents on the quinoline nitrogen atom were obtained by alkylation of 12(H)-quino[3,4-b][1,4]benzothiazine with alkyl bromides. Antiproliferative activity in vitro of the compounds (3) was assessed using two cancer cell lines (Hct116 and LLC) and doxorubicin as a reference. Most of the studied phenothiazine derivatives showed activity against both cell lines investigated (2.2-19.6 μg/mL concentration range). A structure-activity relationship was established. Only the compounds with substituents in the 11-position of the quinobenzothiazine ring did not exhibit activity against either cell line.

1-Alkyl-4-(3-pyridinylamino)quinolinium-3-thiolates and their transformation into new diazaphenothiazine derivatives

The reactions of 5,12-dialkylthioquinantrenediinium bis-salts (1) with 3-aminopyridine yield 1-alkyl-4-(3-pyridinylamino)quinolinium-3-thiolates (2). In the presence of oxygen and hydrogen chloride, the compounds (2) undergo cyclization to 1,4-thiazine derivatives having the structure of 5-alkyl-12(H)-pyrido[2,3-e]quino[3,4-b][1,4]thiazinium salts (4). The structure of 3-thiolates (2) was analyzed using H NMR (NOE) and 15 N NMR spectral methods. The structure of compound (4) was confirmed by X-Ray analysis.

1-Alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium Salts — Synthesis and Transformations

- The reaction of l-alkyl-4-(phenylamino)quinolinium 3-thiolates (2) with benzoyl chloride leads to 1 -alkyl-3-benzoylthio-4-(phenylamino)quinolinium chloride (6). In the presence of DABCO, compounds (6) split off hydrogen chloride yielding l-alkyl-3-benzoylthio-l,4-dihydro-4-(phenylimino)quinoline (7). Alkylation of 4-(phenylimino)quinoline (7) with ethyl bromide leads to 1-alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10). The structure of the obtained compounds were analyzed using H NMR (NOE) and 15 N NMR spectral methods. The structure of compound (lOa) was confirmed by X-ray analysis.

Azinyl sulfides — CXVIII. Antimicrobial activity of novel 1-methyl-3-thio-4-aminoquinolinium salts

Synthesis and antimicrobial activity of novel 1-methyl-3-alkylthio-4-aminoquinolinium salts 2 and 1-methyl-3-acylthio-4-aminoquinolinium salts 4 are described. Compounds 2 were obtained by reacting 1-methyl-3,4-(dimethylthio)quinolinium chloride 1 with amines and by reacting 1-methyl-4-aminoquinolinium-3-thiolates 3 with alkylating agents. Compounds 4 were obtained by the reaction of 1-methyl-4-aminoquinolinium-3-thiolates 3 with acylating agents. Antimicrobial activity of compounds 2 and 4 was determined using G+ (Staphylococcus aureus, Enterococcus faecalis) and G− (Escherichia coli, Pseudomonas aeruginosa) strains as well as Candida albicans yeast. The compounds show greatest activity against S. aureus whereas the lowest against P. aeruginosa.

1-Ethyl-3-methylthio-4-thioxo-1,4-dihydroquinoline or 1-ethyl-3-(methylthio)quinolinium-4-thiolate?

The title compound 1 crystallizes in the monoclinic space group C2/c with a = 16.720(4), b = 8.577(1), c = 15.855(4) Å, and β = 98.37(1)°. The thiocarbonyl group C – S bond (1.697(4) Å) is longer than those of typical carbon–sulfur double bonds in thiones. Bond lengths and bond angles in the pyridine ring of the title compound are close to the values found for pyridinium salts.

Synthesis and In Vitro Antiproliferative Activity of Novel Phenyl Ring-Substituted 5-Alkyl-12(H)-quino[3,4-b][1,4]benzothiazine Derivatives

A novel series of tetracyclic quinobenzothiazine derivatives was synthetized. Compounds containing a substituent (hydroxyl, methyl, phenyl, piperidyl, or piperazinyl) in positions 9 and 11 were obtained by cyclization of suitable 4-aminoquinolinium-3-thiolates. Quinobenzothiazine 10-O-substituted derivatives were obtained by alkylating the hydroxyl group in position 10 of the parent (quinobenzothiazine) system. Antiproliferative activity of the synthesized compounds was studied using cultured neoplastic cells (MDA-MB-231, SNB-19, and C-32 cell lines). Four selected compounds were investigated in more detail for cytotoxicity and antiproliferative effect. Transcriptional activity of genes regulating cell cycle (TP53), apoptosis (BAX, BCL-2), as well as proliferation (H3) were assessed. Finally, the ability of the selected compounds to bind DNA was checked in the presence of ethidium bromide.

An Activity of Thioacyl Derivatives of 4-Aminoquinolinium Salts towards Biofilm Producing and Planktonic Forms of Coagulase-Negative Staphylococci

Microorganisms present in different environments have developed specific mechanisms of settling on various abiotic and biotic surfaces by forming a biofilm. It seems to be well justified to search for new compounds enabling biofilm reduction, which is highly resistant to antibiotics. This study was thus an initial assessment of the antibacterial activity of two new quinoline derivatives of a structure of 3-thioacyl 1-methyl 4-arylaminoquinolinium salts against coagulase-negative staphylococci (CoNS) isolated from a hospital environment, in a form of both biofilms and in planktonic form. Thirty-three stains of CoNS isolated from the hospital environment (air, surfaces) and seven reference strains from the ATCC collection were selected for the study. The mean MIC value for 1-methyl-3-benzoylthio-4-(4-chlorophenylamino)quinolinum chloride (4-chlorophenylamino derivative) was 42.60 ± 19.91 μg/mL, and in the case of strains subjected to 1-methyl-3-benzoylthio-4-(4-fluorophenylamino)quinolinum chloride (4-fluorophenylamino derivative) activity, the mean MIC value was 43.20 ± 14.30 μg/mL. The mean concentration of 4-chlorophenylamino derivative that inhibited biofilm formation was 86.18 ± 30.64 μg/mL. The mean concentration of 4-fluorophenylamino derivatives that inhibited biofilm formation was higher and amounted to 237.09 ± 160.57 μg/mL. Based on the results, both derivatives of the examined compounds exhibit high antimicrobial activity towards strains growing both in planktonic and biofilm form.

Synthesis and Antimicrobial Activity of Sulfur Derivatives of Quinolinium Salts

A novel method for cleavage of the dithiine ring in 5,12-(dimethyl)-thioqinantrenium bis-chloride 1 “via” reaction with sodium hydrosulfide leads to 1-methyl-3-mercaptoquinoline-4(1H)-thione 2. Further transformation of thiol and thione functions of compound 2 leads to a series of sulfide and disulfide derivatives of quinolinium salts 4 and 6. 1-Methyl-4-chloro-3-benzylthioquinoline chloride 8 was obtained by N-alkylating 4-chloro-3-benzylthioquinoline using dimethyl sulfate. Antimicrobial activity of the obtained compounds was investigated using six Gram-positive and six Gram-negative bacterial strains, as well as Candida albicans yeast. Greater activity was demonstrated towards Gram-positive strains. MIC values for compounds and with benzylthio 4d and benzoylthio 4f substituents in 3-quinoline position were found to be in the 0.5–1 μg/mL range, at a level similar to that of ciprofloxacin (reference). Compounds 4d and 4f also demonstrated interesting antifungal properties (MIC = 1).