A diverse series of 43 novel “soft antimicrobials” based on quaternary ammonium pyridoxine derivatives which include six-membered acetals and ketals of pyridoxine bound via cleavable linker moieties ...(amide, ester) with a fragment of fatty carboxylic acid was designed. Nine compounds exhibited in vitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains with MIC values comparable with reference antiseptics miramistin, benzalkonium chloride and chlorohexidine. On various clinical isolates, the lead compounds 6i and 12a exhibited antibacterial activity comparable with that of benzalkonium chloride while higher than that of miramistin. Moreover, 6i and 12a were able to kill bacteria embedded into the matrix of mono- and dual species biofilms. The treatment of bacterial cells by either 6i and 12a lead to fast depolarization of the membrane suggesting that the membrane is an apparent molecular target of compounds. 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic in vivo at acute oral (LD50 > 2000 mg/kg) and cutaneous administration (LD50 > 2500 mg/kg) on mice. Taken together, our data allow suggesting described active compounds as promising starting point for the new antibacterial agents development.
Display omitted
•Design and synthesis of novel “soft antimicrobials” based on quaternary ammonium pyridoxine derivatives.•The compounds exhibited in vitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains.•Lead compounds 6i and 12a exhibited promising antibacterial activity on clinical isolates and bacterial biofilms.•Lead compounds 6i and 12a were non mutagenic neither in SOS-chromotest nor in Ames test and non-toxic in vivo.
A series of 108 novel quaternary bis-ammonium pyridoxine derivatives carrying various substituents at the quaternary nitrogen's and acetal carbon was synthesized. Thirteen compounds exhibited ...antibacterial and antifungal activity (minimum inhibitory concentration (MIC) 0.25-16 µg/mL) comparable or superior than miramistin, benzalkonium chloride, and chlorhexidine. A strong correlation between the lipophilicity and antibacterial activity was found. The most active compounds had logP values in the range of 1-3, while compounds with logP > 6 and logP < 0 were almost inactive. All active compounds demonstrated cytotoxicity comparable with miramistin and chlorhexidine on HEK-293 cells and were three-fold less toxic when compared to benzalkonium chloride. The antibacterial activity of leading compound
on biofilm-embedded
,
,
or
was comparable or even higher than that of the benzalkonium chloride. In vivo
was considerably less toxic (LD
1705 mg/kg) than benzalkonium chloride, miramistine, and chlorhexidine at oral administration on CD-1 mice. An aqueous solution of
(0.2%) was shown to be comparable to reference drugs efficiency on the rat's skin model. The molecular target of
seems to be a cellular membrane as other quaternary ammonium salts. The obtained results make the described quaternary bis-ammonium pyridoxine derivatives promising and lead molecules in the development of the new antiseptics with a broad spectrum of antimicrobial activity.
A series of novel isonicotinoyl hydrazones based on pyridoxine (vitamin B
6
) were synthesized. The synthesized compounds were evaluated for their antimycobacterial activity on
M. tuberculosis
H
37
...Rv strain. The most potent compound
13
showed good activity on H37Rv strain and on clinical isolates of
M. tuberculosis
with multidrug-resistant tuberculosis (TB) profile included first- and second-line drugs. Cytotoxicity studies of compound
13
on human embryonic kidney cells, human liver, human mesenchymal stem cells, and human embryonic lung cells in vitro demonstrated it is 2–3 times less toxicity then isoniazid and 1.5–2 less toxicity than ethambutol and moxifloxacin. Compound
13
showed weak complexation with Fe
3+
ions, low acute toxicity (LD
50
> 2000 mg/kg per os on mice) and the identical to isoniazid and significantly better than ethambutol and moxifloxacin efficacious in the mouse model of drug-sensitive (H37Rv) TB. These facts make him a promising candidate for future developments of antitubercular drugs.
Methods for the preparation of three cyclic 2,3,4-tris(hydroxymethyl)-6-methylpyridin-5-ol acetonides have been developed by variation of the reaction conditions. The six-membered acetonide turned ...out to be thermodynamically more stable than the seven-membered acetonide and bis-acetonide. The experimental data were consistent with the results of quantum-chemical calculations. The structure of the isolated compounds was proved by X-ray analysis.
We report herein the design, synthesis and biological evaluation of series of 7-substituted fluoroquinolones with pyridoxine derivatives. In vitro screening of antibacterial activity and toxicity of ...39 synthesized fluoroquinolones defined compounds 7 and 28 as lead compounds for further investigations. On various clinical isolates lead compounds 7 and 28 exhibited antibacterial activity comparable with reference fluoroqinolones. Mutagenic effects haven't been observed for these compounds in SOS-chromotest. Compound 7 are non-toxic in vivo on mice (LD50 > 2000 mg/kg, oral) and rats (LD50 > 2000 mg/kg, oral). Compound 28 was more toxic (LD50 = 474 mg/kg, oral, mice). Moreover compound 7 showed greater in vivo efficacy compared to ciprofloxacin in a murine model of staphylococcal sepsis. Taken together the described active compound are promising candidate for preclinical trials.
Display omitted
•Synthesis and biological evaluation of fluoroquinolones containing a pyridoxine derivatives moiety•The compounds exhibited in vitro promising antibacterial activity against Gram-positive and Gram-negative bacterial strains.•Lead compound 7 is non-toxic in vivo on mice (LD50 > 2000 mg/kg, oral) and rats (LD50 > 2000 mg/kg, oral) and showed greater in vivo efficacy compared to ciprofloxacin in a murine model of staphylococcal sepsis.
Synthetic approaches to three cyclic 2,4,5,6-tetrakis(hydroxymethyl)pyridin-3-ol acetonides were developed. Among seven possible mono- and diketals, six-membered cyclic ketal incorporating the ...hydroxymethyl group in the 4-position turned out to be the most thermodynamically favorable. The experimental data were consistent with the results of quantum-chemical calculations of the Gibbs energies of formation of different acetonides. The structure of the isolated compounds was studied by X-ray diffraction.
Display omitted
•Twelve pyridoxine-based bioisosteric analogs of dehydrozingerone are synthesized.•At least 8 compounds possess high in vitro antitumor activity and selectivity.•The active compounds ...inhibit migration of tumor cells and arrest their cell cycle.•They also increase the level of reactive oxygen species and initiate apoptosis.•The leading compound also affects the functional activity of mitochondria.
Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase. Similar to DZG, but with higher efficiency, the leading compound was able to inhibit migration activity and, therefore, invasiveness of tumor cells. It also increased concentration of reactive oxygen species in tumor cells, induced depolarization of mitochondrial membranes and initiated apoptosis accompanied by disruption of integrity of cytoplasmic cell membranes. By contrast to DZG, the leading compound did not possess antioxidant properties. The obtained data make the described chemotype a promising starting point for the development of new anticancer agents.
We synthesized a number of new derivatives of phenolic glycoside saccharumoside-B based on pyridoxine and 3-hydroxy-2-methylpyridine and studied their cytotoxicity
in vitro
against three normal ...(HEK-293, Chang Liver, MSC) and nine tumor (MCF-7, MDA-MB-231, A-498, SNB-19, M-14, NCI-H322M, HCT-115, HCT-116, PC-3) human cell lines compared with camptothecin, doxorubicin, and saccharumoside-B. The effect of the peripheral fragments of phenolic glycoside on the target activity was studied and the structure—antitumor activity relationship was established. A new efficient approach to the synthesis of saccharumoside-B was proposed.
Several pyridoxine azo derivatives have been synthesized and their
in vitro
antiglycation activity has been studied. It has been found that the synthesized compounds are more active in terms of IC
50
...than aminoguanidine (by factors of 6–21) and pyridoxamine (by factors of 1.8–5.6). The
in vivo
study of acute toxicity of the most potent compound has shown their safety (LD
50
> 2000 mg/kg).
PDF
