Antibacterial diterpenoids from Sagittaria pygmaea

There were five new diterpenoids, 18-beta-D-3',4'-diacetoxyxylopyranosyl-ent-kaur-16-ene (1), 18-beta-L-3',5'-diacetoxyarabinofuranosyl-ent-kaur-16-ene (2), 18-beta-D-3',6'-diacetoxyglucopyranosyl-ent-kaur-16-ene (3), ent-isopimar-8(14),15-dien-19-oic acid (4), and 5alpha-hydroxy-ent-rosa-15-en-18-oic acid (5), isolated from the whole herb of Sagittaria pygmaea. Their structures and relative configurations were established based on spectroscopic studies, chemical methods, and X-ray crystallographic analysis. Compound 2 exhibited significant antibacterial activity against the oral pathogens, Streptococcus mutans ATCC 25 175 and Actinomyces viscosus ATCC 27 044, with MIC values against both pathogens of 15.6 microg/mL. Compound 3 was active against only A. viscosus ATCC 27 044 with an MIC value of 62.5 microg/mL. Compounds 4 and 5 were active against S. mutans ATCC 25 175 and A. viscosus ATCC 27 044, with MIC values against both pathogens of 125.0 microg/mL.     

Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents

A series of 2-{[2'-(3'-chloro-2'-oxo-4'-substitutedaryl-1'-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2'-substitutedaryl-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2'-p-hydroxy-m-methoxyphenyl)-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.     

Antimicrobial and anti-plaque activity of N'-alkyl-N-(2-aminoethyl)piperidine against dental plaque bacteria

Five N'-alkyl-N-(2-aminoethyl)piperidines were synthesized and their in vitro antimicrobial activities were tested against four micro-organisms related to dental caries (Streptococcus mutans, S. sobrinus, Actinomyces viscosus, and A. naeslundii) which are known to be implicated in dental caries. The tetradecyl and hexadecyl derivatives possessed good bacteriostatic activity. Some derivatives exhibited a rapid bactericidal effect against S. mutans and S. sobrinus in aqueous solution. These compounds also possessed surfactant properties and anti-plaque activity.     

Synthesis and antibacterial activity of substituted oxotriazolylphenyl oxazolidinones

A series of 3-(4'-(2'-alkyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-substituted oxazolidinones was designed and synthesized for in vitro antibacterial activity testing against fourteen Gram-negative and six Gram-positive standard organisms. The minimum inhibitory concentration (MIC) was determined by agar dilution at concentrations of 0.10, 0.20, 0.39, 0.78, 1.56, 3.13, 6.25 microg/mL. Different alkyl groups at the 2'-position played an important role in the activity against Gram-positive organisms. (S)-3-(4'-(2'-ethyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-acetamidomethyloxazolidinone was active against Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus enteridis and Streptococcus nonhemolyticus, whereas 2'-methyl, 2'-propyl and 2'-n-butyl counterparts did not show activity at 6.25 microg/mL. Modification of the 5-substitutent of oxazolidinones also affected the activity against Gram-positive organisms. (S)-3-(4'-(2'-ethyl-3'-oxy-1',2',4'-triazolyl)-phenyl)-5-acetamidomethyloxazolidinones was approximately two fold more potent than 5-chloroacetamido, 5-dichloroacetamido and 5-trifluoroacetamido counterparts against Streptococcus enteridis. None of these compounds showed growth inhibition against fourteen Gram-negative organisms at 6.25 microg/mL.     

Synthesis and activity of potent 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins.

The syntheses and in vitro antibacterial activities of 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins are described. 1,3-Dipolar cycloaddition of 3-vinylcephalosporin with nitrone gave diastereomeric isomers of 3-(isoxazolidin-5-yl)cephalosporin. The antibacterial activities of 3'-(S)-isomers were superior to those of 3'-(R)-isomers. The quaternarization of isoxazolidine ring increased the antibacterial activity. Among them, compound 10b with a hydroxyimino group in the C-7 side chain showed potent activities against staphylococci and compound 10f with an N-hydroxypyridone exhibited an excellent antipseudomonal activity.     

Substituted 2-(2-hydroxyphenyl)benzimidazoles as potential agents for the control of periodontal diseases

A series of 16 substituted 2-(2-hydroxphenyl)benzimidazoles was synthesized and evaluated in vitro for antibacterial activity against bacteria associated with periodontal diseases. Several compounds demonstrated a high level of activity, in tube dilution assay, against Actinomycetes viscosus and Bacteriodes gingivalis. These results indicate that several of these compounds may serve as topical antibacterial agents for the control of acute marginal inflammatory gingivitis and periodontitis.     

Antimicrobial activity of tanzanian chewing sticks against oral pathogenic microbes

Methanol extracts from the bark and wood of ten plants used as chewing sticks in Morogoro region, in Tanzania, were tested for their ability to inhibit the growth of cariogenic bacteria, Streptococcus mutans , Actinomyces viscosus and a yeast Candida albicans . Screening for antimicrobial activity was done by the agar-hole diffusion method, and minimum inhibitory concentrations (MICs) were determined by the agar dilution method. Extracts from seven out of the ten plants showed varying degrees of growth inhibitory effect on the microorganisms, with Acacia senegal var. senegal stem bark being the most active, followed by the stem bark of Eriosema psoraleoides . Their MICs ranged from 0.63 mg/ml to 5 mg/ml. Three plants Ocimum suave , Opilia celtidifolia and Xerophyta suaveolens did not exhibit any antimicrobial effect. Actinomyces viscosus was relatively more sensitive to the extracts than S. mutans and C. albicans . This study has also demonstrated that most bark extracts possessed antimicrobial activity, while many wood extracts were inactive. It is, therefore, advisable to use, for toothbrushing, unpeeled, rather than peeled chewing sticks, in order to exploit fully their antimicrobial effect. However, additional studies are needed to determine their antiplaque, anticaries and antimycotic effects.     

Antimicrobial Activity of Tanzanian Chewing Sticks Against Oral Pathogenic Microbes

Methanol extracts from the bark and wood of ten plants used as chewing sticks in Morogoro region, in Tanzania, were tested for their ability to inhibit the growth of cariogenic bacteria, Streptococcus mutans , Actinomyces viscosus and a yeast Candida albicans . Screening for antimicrobial activity was done by the agar-hole diffusion method, and minimum inhibitory concentrations (MICs) were determined by the agar dilution method. Extracts from seven out of the ten plants showed varying degrees of growth inhibitory effect on the microorganisms, with Acacia senegal var. senegal stem bark being the most active, followed by the stem bark of Eriosema psoraleoides . Their MICs ranged from 0.63 mg/ml to 5 mg/ml. Three plants Ocimum suave , Opilia celtidifolia and Xerophyta suaveolens did not exhibit any antimicrobial effect. Actinomyces viscosus was relatively more sensitive to the extracts than S. mutans and C. albicans . This study has also demonstrated that most bark extracts possessed antimicrobial activity, while many wood extracts were inactive. It is, therefore, advisable to use, for toothbrushing, unpeeled, rather than peeled chewing sticks, in order to exploit fully their antimicrobial effect. However, additional studies are needed to determine their antiplaque, anticaries and antimycotic effects.     

In vitro antimalarial activity of novel trifluoromethyl- and bis(trifluoromethyl)quinoline derivatives

The in vitro antimalarial activity of a series of 2- and 8-trifluoromethyl- and 2,8-bis(trifluoromethyl)quinoline-4-(5-pyrimidino) and N4-ethyl-5-nitroimidazolo)methylene ketones was assessed against the chloroquine-sensitive strain (D10) of Plasmodium falciparum. Although the in vitro antimalarial activity of these compounds is more or less of the same order of magnitude, derivatives containing two trifluoromethyl groups achieve a slightly higher in vitro activity than compounds with one trifluoromethyl group, with 2,8-bis(trifluoromethyl) quinoline-4-(N4-ethyl-5-nitroimidazolo) methylene and 2,8-bis(trifluoromethyl) quinoline-4-(5-pyrimidino) ketones showing IC50 of 4.8 and 5.2 micrograms/ml, respectively. These compounds seem to bind to DNA by intercalation.     

Antimicrobial activity of N-alkylethylenediamines against oral and other microorganisms

Six N-alkylethylenediamines were synthesized and antimicrobial activity of each compound against oral microorganisms such as Streptococcus mutans, Actinomyces viscosus and Actinomyces naeslundii, and some others were determined in vitro. Dodecyl or tetradecyl derivative possessed maximum bacteriostatic activity among the test compounds. On the other hand, killing time of S. mutans in aqueous solution decreased with increasing alkyl-chain length.     

Synthesis and in vitro evaluation of substituted phenyl-piperazinyl-phenyl oxazolidinones against Gram-positive bacteria

With the incidence of linezolid-resistant Enterococcus faecalis, E. faecium and Staphylococcus aureus, modification of linezolid at the 5- and/or 3-positions led to the development of a series of 3-(methoxyl-phenyl)-piperazinyl-phenyl oxazolidinone analogues. These compounds were tested in vitro against six gram-positive standard organisms (S. aureus, S. epidermidis, S. pneumoniae, S. albus, Streptococcus enteridis and S. nonhemolyticus). 5-acetylaminomethyl oxazolidinones bearing fluorine at 3'-position of phenyl ring showed activities against several gram-positive bacteria (MIC: 3.13-6.25 mug/mL). The position of methoxyl group on the phenyl ring of piperazine group affected antibacterial spectrum. 3-(4'- (para-methoxyl-phenyl)-piperazinyl)-(3'-fluoro)-phenyl-5-acetylaminomethyl oxazolidinone was found active against 5 gram-positive organisms except S. nonhemolyticus, whereas 3-(4'-(ortho-methoxyl-phenyl)-piperazinyl)-(3'-fluoro)-phenyl-5-acetylaminomethyl oxazolidinone was found active only against 2 gram-positive organisms, namely S. albus, S. enteridis.     

Synthesis and biological activity of some 2-aminoimidazoles

A review of the literature showed that 2-amino-imidazoles have not benn taken into consideration as antimicrobial agents. Our preliminary data indicating that 2-amino-4(5)-phenylimidazole possessed a moderate in vitro activity prompted us to prepare a limited series of 2-amino-4(5)-arylimidazoles and of some related derivatives. In vitro atimicrobial screening gave evidence of a broad spectrum activity for some of them. Several compounds have been tested also against S. mutans. In particular, 2-amino-4(5)-(4-biphenylyl)-imidazole hydrochloride showed substantial activity in this test, confirmed also against defferent representative strains of S. mutans. When submitted to a plaque inhibition test, it strongly inhibited the plaque forming ability of a S. mutans strain.     

The oriented development of antituberculotics: salicylanilides

On the basis of our previous results 22 salicylanilides were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The Free-Wilson method was used to evaluate structure-antimycobacterial activity relationships. 4-Chloro-N-(4-propylphenyl)salicylamide and 5-chloro-N-(4-propylphenyl)salicylamide were selected for preclinical studies.     

Antistaphylococcal activity of novel salicylanilide derivatives

This study examined the antibacterial properties of nineteen benzoxazole, isoniazid, ethionamide and salicylanilide derivatives against Staphylococcus aureus (S. aureus). It was found that three salicylanilide-derived compounds demonstrated antistaphylococcal activity: 5-Chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (5-Cl-4'-CF3- SAL), 4-chloro-2-(3-chlorophenylcarbamyoyl)phenyl)-2-(benzyloxycarbonylamino)propanoate (AIM31) and 4-chloro-2- (4-(trifluoromethyl)phenylcarbamoyl)phenyl acetate (AIM33). Investigation of the chemical structures of these three compounds and comparison with a non-inhibitory salicylanilide compound (i.e. 5,3'-diCl-SAL) illustrated that different combinations of chemical groups at defined positions on the salicylanilide core structure had a marked influence on antistaphylococcal activity. The most effective compound was AIM33 which inhibited staphylococcal growth and displayed an initial MIC value of 3.12 μg ml(-1) and subsequent investigation revealed that an MIC as low as of 0.5 μg ml(-1) was achievable. In this case, the dual presence of a trifluoromethyl group and an acetylated phenolic hydroxyl to the salicylanilide core structure led to greatly enhanced activity.     

Synthesis and antimicrobial activity of some thiazolinyl tetrahydrobenzo[b]thiophenes and thiazolinyl tetrahydrobenzothieno[2,3-d]pyrimidin-4-ones.

Two series of novel 3-carbethoxy-2-(3',4'-disubstituted-2',3'- dihydrothiazol-2'-ylidenamino)-4,5,6,7-tetrahydrobenzo[b] thiophenes (3a-o) and 2-methyl-3-(3',4'-disubstituted-2',3'-dihydrothiazol-2'-ylidena mino-5,6,7,8- tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H) ones (8a-o) have been synthesized and tested for antimicrobial activity. All members of the series have been found to exhibit in vitro antibacterial and/or antifungal activities. Activity was optimized by cyclization to the thienopyrimidin-4-ones. In particular, compounds 8e and 8fd were the most active against the 3 tested microorganisms. Their antifungal activity was higher than that exhibited by nystatin while their MIC was found to be nearly equal to that of nystatin.     

4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues as potential antimalarial agents

Five 4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues were synthesized and tested for radical curative activity against Plasmodium cynomolgi in Rhesus monkeys and for blood schizonticidal antimalarial activity against Plasmodium berghei in mice. In addition, they were evaluated for causal prophylactic antimalarial activity against Plasmodium berghei yoelii in mice. One compound, 4-ethyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2b), showed radical curative activity equivalent to 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2a). A second compound showed radical curative activity slightly less than 2a and 2b; the remaining three compounds were not active against P. cynomolgi. All five compounds showed much higher blood schizonticidal activity and less toxicity than primaquine; however, none of the compounds were as active as 2a. Three of four compounds tested showed high activity against P. berghei yoelii.     

In vitro anti-cariogenic activity of dichloromethane fraction fromRheum undulatum L. root

This study aimed to evaluate in vitro effects of Rheum undulatum L. root on the development of dental caries, especially its effects on viability, dental plaque formation, and glycolytic acid production of Streptococcus mutans and Streptococcus sobrinus. Methanol extract of Rheum undulatum L. root and its fractions were prepared and tested. Among the test extract and fractions, dichloromethane fraction (DF) showed the most active antibacterial activity (inhibition zone: 13-17 mm) against S. mutans and S. sobrinus in a disc diffusion method. Minimal inhibitory concentrations (MICs) of DF against these bacteria ranged from 0.25 to 0.5 mg/mL. Furthermore, DF significantly inhibited the caries-inducing factors of these bacteria. At sub-MIC levels, DF inhibited in vitro dental plaque formation by S. mutans and S. sobrinus (IC50= 0.079 and 0.142 mg/mL, respectively), which was caused, in part, by the inhibitory effect on the activity of glucosyltransferases. A significant reduction of glycolytic acid production was found at the concentration as low as 0.032 mg/mL for S. mutans and 0.063 mg/mL for S. sobrinus. The possible bioactive compounds that are inducing in vitro anti-cariogenic activity of DF are unknown. Based on the preliminary phytochemical analysis, the activity of DF may be related to the presence of anthraquinones, cardiac glycosides, coumarines, sterols/terpenes, and phenolics. These results indicate that DF is probably useful for the control of dental plaque formation and subsequent dental caries development.     

New 8-(trifluoromethyl)-substituted quinolones. The benefits of the 8-fluoro group with reduced phototoxic risk.

A series of 8-(trifluoromethyl)-substituted quinolones has been prepared and evaluated for in vitro and in vivo antibacterial activity, and phototolerance in a mouse phototolerance assay. These analogues were compared to the corresponding series of 6,8-difluoro- and 6-fluoro-8H-quinolones (ciprofloxacin type). Although their in vitro antibacterial activities are less than the 6,8-difluoro analogues, the 8-(trifluoromethyl)quinolones are generally equivalent to their 8H analogues. In vivo, they are comparable to the 6,8-difluoro series and show up to 10-fold improvement in efficacy when compared to their ciprofloxacin counterparts vs Streptococcus pyogenes and Streptococcus pneumonia. In the phototolerance model, the 8-(trifluoromethyl)quinolones are comparable to the 8H-quinolones. Both of these series display much higher no effect doses (greater tolerance) than the corresponding 6,8-difluoroquinolones.     

Rotationally restricted mimics of rigid molecules: nonspirocyclic hydantoin aldose reductase inhibitors

Sorbinil (1), a spirocyclic hydantoin, is a potent inhibitor of the enzyme aldose reductase. Simulation of the rigid spirocyclic ring orientation found in sorbinil was achieved with nonspirocyclic 5-[5'-chloro-2'-(alkylsulfonyl)-phenyl]hydantoins and 5-[5'-chloro-2'-[(N-alkylamino)sulfonyl]phenyl]hydantoins. The 2'-substituent (SO2R) was sufficiently large to hinder rotation of the hydantoin ring, forcing an orientation similar to that of a spirocyclic hydantoin. Calculated conformational preference, X-ray data, and inhibitory IC50 values for these nonspirocyclic 2'-substituted (SO2R) phenylhydantoins are in accord with what is expected for spirocyclic hydantoins and comparable to those of sorbinil.     

Antimicrobial activity of trifluoromethyl ketones and their synergism with promethazine

The antimicrobial effects of 30 trifluoromethyl ketones [1-30] were studied on various representative bacteria. Of the ketones, 4,4,4-trifluoro-1-phenyl-1,3-butanedione [10], 1,1,1-trifluoro-3-(4,5-dimethyloxazol-2-yl)-2-propanone [11] and 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone [18] were found to exhibit potent antibacterial activity against the Gram-positive Bacillus megaterium and Corynebacterium michiganese, but not against Gram-negative bacteria such as Pseudomonas aeruginosa and Serratia marcescens. Compounds 11 and 18 inhibited the Escherichia coli. Compound 18 was also effective against yeasts. The combination of promethazine with 18 was significantly synergistic against E. coli strains, especially the proton pump deficient mutant. The results suggest that membrane transporters are the target of trifluoromethyl ketones. The inhibition was more marked in the proton pump deficient E. coli mutant than in the wild type, which suggested that the antibacterial effect of trifluoromethyl ketones is partly prevented by the proton pump system.