Ales Imramovsky

Salicylanilide Acetates: Synthesis and Antibacterial Evaluation

A new series of salicylanilide acetates was synthesized and evaluated for their in vitro antifungal and antituberculotic activity. Some of the evaluated compounds possessed comparable or better antifungal activity than a fluconazole standard. All these compounds exhibited very good potential and their in vitro activity against drug resistant and sensitive clinical isolates of Mycobacteria were found to be equivalent or better than a standard of isoniazide, a well-known first-line drug for tuberculosis treatment.

Investigating the spectrum of biological activity of substituted quinoline-2-carboxamides and their isosteres.

In this study, a series of thirty-five substituted quinoline-2-carboxamides and thirty-three substituted naphthalene-2-carboxamides were prepared and characterized. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial species. N-Cycloheptylquinoline-2-carboxamide, N-cyclohexylquinoline-2-carboxamide and N-(2-phenylethyl)quinoline-2-carboxamide showed higher activity against M. tuberculosis than the standards isoniazid or pyrazinamide and 2-(pyrrolidin-1-ylcarbonyl)quinoline and 1-(2-naphthoyl)pyrrolidine expressed higher activity against M. kansasii and M. avium paratuberculosis than the standards isoniazid or pyrazinamide. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound N-benzyl-2-naphthamide was 7.5 μmol/L. For all compounds, the structure-activity relationships are discussed.

Recent Advances on Isoniazide Derivatives

Tuberculosis remains the leading cause of mortality worldwide even in the 21st century. This review summarises all facts concerning a front-line antituberculotic drug isoniazide – metabolism, mechanism of activity and resistance. The antimycobacterial pharmacophore moiety of isoniazide has been introduced in a number of various types of molecules (about 510 derivatives have been found) to improve their activity against Mycobacteria species, as well as their multidrug-resistant strains. Several Schiff bases, hydrazones, hydrazides and metal complexes of isoniazide have shown very good activity. Various types of the most active isoniazide derivatives classified according to their structure are reported, their lipophilicity has been calculated and structure-activity relationships are discussed. The original new highly active isoniazide prodrug forms prepared at the Faculty of Pharmacy, Charles University, Czech Republic are presented in a separate chapter of the paper.

Investigating Spectrum of Biological Activity of 4- and 5-Chloro-2-hydroxy-N-(2-(arylamino)-1-alkyl-2- oxoethyl)benzamides

In this study, a series of twenty-two 5-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides and ten 4-chloro-2-hydroxy-N-[2-(arylamino)-1-alkyl-2-oxoethyl]benzamides is described. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against mycobacterial, bacterial and fungal strains. They were also evaluated for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The compounds showed biological activity comparable with or higher than the standards isoniazid, fluconazole, penicillin G or ciprofloxacin. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.

Salicylanilide carbamates: Promising antibacterial agents with high in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)

A series of twenty-one salicylanilide N-alkylcarbamates was assessed for novel antibacterial characteristics against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213 as the reference and quality control strain. The minimum inhibitory concentration was determined by the broth dilution micro-method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The bactericidal kinetics was established by time-kill assay. Ampicillin, ciprofloxacin and vancomycin were used as reference antibacterial drugs. All the tested compounds exhibited highly potent anti-MRSA activity (⩽ 0.008-4 μg/mL) comparable or up to 250× higher than that of vancomycin, the standard in the treatment of serious MRSA infections. 4-Chloro-2-(3,4-dichlorophenylcarbamoyl)phenyl butylcarbamate and 4-chloro-2-(3,4-dichlorophenylcarbamoyl)phenyl ethylcarbamate were the most active compounds. In most cases, compounds provided reliable bacteriostatic activity, except for 4-chloro-2-(4-chlorophenylcarbamoyl)phenyl decylcarbamate exhibiting bactericidal effect at 8h (for clinical isolate of MRSA 63718) and at 24h (for clinical isolates of MRSA SA 630 and MRSA SA 3202) at 4× MIC. Structure-activity relationships are discussed.

1,3-substituted imidazolidine-2,4,5-triones: synthesis and inhibition of cholinergic enzymes.

A series of novel and highly active acetylcholinesterase and butyrylcholinesterase inhibitors derived from substituted benzothiazoles containing an imidazolidine-2,4,5-trione moiety were synthesized and characterized. The molecular structure of 1-(2,6-diisopropyl-phenyl)-3-[(1R)-1-(6-fluoro-1,3-benzothiazol-2-yl)ethyl]-imidazolidine-2,4,5-trione (3g) was determined by single-crystal X-ray diffraction. Both optical isomers are present as two independent molecules in the triclinic crystal system. The lipophilicity of the compounds was determined as the partition coefficient log Kow using the traditional shake-flask method. The in vitro inhibitory activity on acetylcholinesterase from electric eel and butyrylcholinesterase isolated from equine serum was determined. The inhibitory activity on acetylcholinesterase was significantly higher than that of the standard drug rivastigmine. The discussed compounds are also promising inhibitors of butyrylcholinesterase, as some of the prepared compounds inhibit butyrylcholinesterase better than the internal standards rivastigmine and galanthamine. The highest inhibitory activity (IC50 = 1.66 μmol/L) corresponds to the compound 1-(4-isopropylphenyl)-3-[(R)-1-(6-fluorobenzo[d]thiazol-2-yl)ethyl]imidazolidine-2,4,5-trione (3d). For all the studied compounds, the relationships between the lipophilicity and the chemical structure as well as their structure-activity relationships are discussed.

In Vitro Bactericidal Activity of 4- and 5-Chloro-2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]benzamides against MRSA

A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S)-3-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (1f), N-{(2S)-1-[(4-bromophenyl)amino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g), and 4-chloro-N-{(2S)-1-[(3,4-dichlorophenyl)amino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (1h) was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL) and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count) after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h.

Microwave-Assisted Synthesis of New Substituted Anilides of Quinaldic Acid

In this study a one step method for the preparation of substituted anilides of quinoline-2-carboxylic acid was developed. This efficient innovative approach is based on the direct reaction of an acid or ester with substituted anilines using microwave irradiation. The optimized method was used for the synthesis of a series of eighteen substituted quinoline-2-carboxanilides. The molecular structure of N-(4-bromophenyl)quinoline-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. It crystallizes in the monoclinic space group with four molecules within the unit cell and the total structure of the compound can be described as “a slightly screwed boat”.

Antimycobacterial and Photosynthetic Electron Transport Inhibiting Activity of Ring-Substituted 4-Arylamino-7-Chloroquinolinium Chlorides

In this study, a series of twenty-five ring-substituted 4-arylamino-7-chloroquinolinium chlorides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts and also primary in vitro screening of the synthesized compounds was performed against mycobacterial species. 4-[(2-Bromophenyl)amino]-7-chloroquinolinium chloride showed high biological activity against M. marinum, M. kansasii, M. smegmatis and 7-chloro-4-[(2-methylphenyl)amino]quinolinium chloride demonstrated noteworthy biological activity against M. smegmatis and M. avium subsp. paratuberculosis. The most effective compounds demonstrated quite low toxicity (LD50 > 20 μmol/L) against the human monocytic leukemia THP-1 cell line within preliminary in vitro cytotoxicity screening. The tested compounds were found to inhibit PET in photosystem II. The PET-inhibiting activity expressed by IC50 value of the most active compound 7-chloro-4-[(3-trifluoromethylphenyl)amino]quinolinium chloride was 27 μmol/L and PET-inhibiting activity of ortho-substituted compounds was significantly lower than this of meta- and para-substituted ones. The structure-activity relationships are discussed for all compounds.

Salicylanilides and Their Derivates as Perspective Anti-tuberculosis Drugs: Synthetic Routes and Biological Evaluations

Abstract: Salicylanilides are a well-known family of pharmacological compounds, which are under renewed investigation because of the discovery of novel interesting biological activities and mechanisms of action over the last decade. This comprehensive mini-review de-scribes the biological and pharmacological properties of salicylanilides, their activity against atypical and multi-drug resist ant mycobacte-rial strains, and synthetic routes for their preparation. In particular, this review focuses on the synthesis and biological properties of sali-cylanilides and O -substituted derivates reported between 2000 and 2010, which have displayed the highest antituberculosis or antifungal activity. Keywords: Anti-MDR tuberculotics, anti-tuberculotic agents, hydroxybenzamides, salicylan ilides, salicylanilide derivates. 1. INTRODUCTION Salicylanilides ( N -substituted hydroxy benzamides) are well-known organic pharmacological compounds with numerous bio-logical activities, which were initially investigated for their antimi-crobial [1] and antifungal activities [2], as well as their usefulness as topical antimycotics and antiplaque agents [3]. Salicylanilides have also found use as molluscicidal [4] or anthelmintic agents [5] in human and veterinary practise. The most successful of these, 5,2´-dichloro-4´-nitrosalicylanilide (Niclosamide), is a member of a group of common molluscicides [6] with anthelmintic properties, and is also effective in the treatment of diphyllobothriasis and hy-menolepiasis [7]. Closantel is another broad-spectrum anthelmintic salicylanilide, which has been used as an anti-trematode, anti-nematode and anti-arthropod, in combination with benzimidazole anthelmintics such as Mebendazole [8]. Rafoxanide is highly active against