QSAR, diagnostic statistics and molecular modelling of 1,4-dihydropyridine calcium antagonists: a difficult road ahead.

Quantitative structure-activity relationships of a series of substituted 1,4-dihydropyridine calcium channel antagonists were studied. The analysis is difficult because of the problem of multicollinearity of substituent parameters, a high-leverage point, and position-dependent grouped observations. Canonical regression appears to be the method of choice. With respect to a maximum activity, it was shown that the following rank order of substituent parameters exists: Lipophilicity approximately ortho-position > inductivity > minimum width > meta-position. The molecular conformation of antagonists does not differ markedly (with exception of nifedipine derivatives and nimodipine), but differences seem to exist between the antagonists and the activator BAY K 8644.

1,4-Dihydropyridine antagonist activities at the calcium channel: a quantitative structure-activity relationship approach.

The effect of 46 1,4-dihydropyridine-type calcium channel antagonists on the tonic contractile response of longitudinal muscle strips of guinea pig ileum was determined. 2,6-Dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine (13) and 13 ortho-, 15 meta-, and seven para-monosubstituted and 10 polysubstituted aromatic derivatives of 13 were studied. The pharmacological activities of the monosubstituted derivatives were best correlated by eq 10, log 1/C = 0.68 pi + 2.50 sigma m -0.47Lmeta -3.40B1para + 11.31, which had a correlation coefficient of 0.89. The full data set was best correlated by eq 11, log 1/C = 0.62 pi + 1.96 sigma m -0.44Lmeta -3.26B1para -1.51Lmeta' + 14.23, which had a correlation coefficient of 0.90. Equations of similar form but involving an ortho steric term were found to correlate the radioligand binding data for this class of compounds.

Structural determinants of activity of chlorhexidine and alkyl bisbiguanides against the human oral flora.

We assayed chlorhexidine and a series of its analogues, in which the chlorophenyl terminal substituents were replaced with alkyl chains, for their in vitro antimicrobial activity against the Gram-negative and Gram-positive oral bacteria. Changes in antimicrobial activity were correlated with changes in agent structure for identification of structural criteria which may be important in the optimization of agent activity. Chlorhexidine showed substantial antimicrobial activity against the Gram-negative as well as the Gram-positive oral bacteria. The alkyl agents were comparable with chlorhexidine in their activity against Bacteroides gingivalis and Bacteroides intermedius, black-pigmented Gram-negative obligate anaerobes associated with periodontal disease in adults. Alkyl agents alexidine, heptihexidine (1,6-bis-n-heptylbiguanidohexane), hexoctidine (1,8-bis-n-hexylbiguanidoctane), and hexhexidine (1,6-bis-n-hexylbiguanidohexane), as well as chlorhexidine, were active against Actinobacillus actinomycetemcomitans, a Gram-negative organism associated with localized juvenile periodontitis. Hexidecidine (1,10-bis-n-hexylbiguanidodecane) and heptoctidine (1,8-bis-n-heptylbiguanidooctane) were more active, and hexhexidine was as active as chlorhexidine against Fusobacterium nucleatum, also associated with periodontal disease. Seven of the agents were more active than chlorhexidine against Actinomyces species. All test agents were active against Streptococcus mutans, a Gram-positive coccus associated with dental caries. Hexidecidine had activity equal to that of chlorhexidine when evaluated against the entire battery of organisms. Analysis of structure-activity relationships revealed that alkyl chains could replace chlorophenyl groups with retention or improvement of antimicrobial activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

5-(Alkylsulfonyl)salicylanilides as potential dental antiplaque agents.

A series of 22 5-(alkylsulfonyl)salicylanilides was synthesized and evaluated for in vitro antibacterial and antiplaque activity against Actinomyces viscosus and Streptococcus mutans, adherent microorganisms implicated in periodontal disease and dental caries. The minimum inhibitory concentrations of 25 salicylanilides (including 5-acyl-, 5-alkyl-, and 5-(alkylsulfonyl)-4'-bromo- and -4'-(trifluoromethyl)salicylanilides) were found to correlate (r = 0.94) with estimated log D values. Several salicylanilides, such as 5-(decylsulfonyl)- and 5-(dodecylsulfonyl)-4'-(trifluoromethyl)salicylanilides (15 and 19) were found to exhibit high levels of in vitro antibacterial and antiplaque activity against A. viscosus and S. mutans.

Tetracycline and its derivatives strongly bind to and are released from the tooth surface in active form.

Several antibiotics were found to adsorb to saliva-coated enamel and to inhibit in vitro plaque formation by pure cultures of oral bacteria: Actinomyces viscosus, Actinomyces naeslundii and Streptococcus mutans. Tetracycline, minocycline and oxytetracycline adsorbed to the greatest degree, showing 100-fold higher adsorption than spiramycin, the test antibiotics with least adsorption. Inhibition of in vitro plaque formation was found to require both drug substantivity (capacity for adsorption) and antimicrobial activity. Inhibition of plaque formation in the in vitro assay employed correlated well with clinical efficacy.

Synthesis and in vitro antimicrobial activity of 5-substituted 2H-1,3,5-thiadiazine-2,4(3H)-diones.

A series of 6-substituted 2H-1,3,5-thiadiazine-2,4(3H)-diones (1a-m) was prepared by treatment of alkyl, aryl, and heterocyclic primary thioamides with phenoxycarbonyl isocyanate to give N-(phenoxycarbonyl)-N'-thioacylureas, which gave 1 upon heating in refluxing xylene solution or upon treatment with aqueous sodium carbonate solution followed by acidification. 1H NMR and infrared spectral evidence indicates that the 6-alkyl derivatives 1a,b,l,m exist predominately in the exocyclic alkylidene tautomeric form. The major product obtained from alkaline and acid hydrolysis of the 6-phenyl derivative 1c was found to be benzoic acid and benzoylurea, respectively. The majority of compounds 1a-m exhibited in vitro antifungal activity against Candida albicans and Trichophyton mentagrophytes. Several derivatives, 1b-d,h,j, displayed minimum inhibitory concentration values below 2 micrograms/mL against Trichophyton mentagrophytes. Four derivatives, 1c,e,g,h, inhibited the growth of Seratia marcesens, Staphylococcus aureus, and Staphylococcus epidermis in an in vitro sensitivity disk assay. 2-Furyl derivative 1h displayed antileukemic activity against P-388 lymphocytic leukemia.

Preliminary evaluation of mesoionic 6-substituted 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones as potential novel prodrugs of methimazole.

A series of five 6-alkyl- and 6-aryl-mesoionic 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones was synthesized and found to produce 1-methyl-3H-imidazole-2-thione (methimazole) upon alkaline hydrolysis or treatment with amine or thiol reagents. The alkaline hydrolysis followed a second-order rate expression, being dependent on both substrate and hydroxide-ion concentrations. The rate constants for the five derivatives fell within 6-15 x 10(-2) liter/mole min at 40 degrees. These compounds were stable in aqueous acidic solutions and in human serum or rat liver homogenate under conditions producing rapid hydrolysis of the methimazole prodrug 1-carbethoxy-2-methylimidazole-2-thione (carbimazole).

Potential salicylamide antiplaque agents: in vitro antibacterial activity against Actinomyces viscosus.

A series of 55 salicylamides, including 3,5-dibromo-, 5-n-alkyl-, and 5-n-acylsalicyloyl derivatives of various anilines, heterocyclic amines, benzylamines, and alkylamines, was synthesized and evaluated for in vitro antibacterial activity against Actinomyces viscosus, an adherent oral microorganism implicated in periodontal disease. The in vitro minimum inhibitory concentrations of 15 4'-bromosalicylanilides were found to correlate (r = 0.92) with estimated log D values. Several nonhalogenated salicylanilides, such as 5-n-hexyl- (40) and 5-n-decanoyl-4'-nitrosalicylanilide (47), were found to exhibit higher levels of in vitro antibacterial activity against a number of Actinomycetes than did tribromsalan (1) or fluorophene (2).

In vitro testing of plaque control agents.

The development of a number of in vitro techniques for the evaluation of antiplaque effects of test agents has followed the characterization and culturing of plaque-forming microorganisms. Studies of the mechanism of action of chlorhexidine and clinical observations have assisted in defining critical aspects of these in vitro techniques. Such assays may play an increasingly important role in screening potential new agents as well as in the optimization of properties by chemical modification of new lead agents. In addition, data generated in the in vitro assay may assist the design of in vivo evaluations of new agents. Proper selection of in vitro techniques for these various functions in the pre-clinical development process may reduce the time and cost involved in the development of new antiplaque agents.

The in vitro inhibition of microbial growth and plaque formation by surfactant drugs.

Several cationic, mixed and amphoteric surfactants were tested for their antimicrobial activity and ability to inhibit the formation of in vitro plaque by oral microorganisms. All had antimicrobial activity against Actinomyces viscosus. Actinomyces naeslundii and Streptococcus mutans. Cationic surfactants were comparable to chlorhexidine in antimicrobial activity but were less effective in inhibiting plaque formation. Amphoteric surfactants were less effective than other detergents in antibacterial activity and had very limited capacity for the inhibition of plaque formation. Comparison of drug structure provides evidence that surfactant substantivity to saliva-coated enamel is a cation active process. Saliva was found to have an antagonistic effect on the activity of cetylpyridinium chloride but not on Triburon.

In vitro antiplaque properties of a series of alkyl bis(biguanides).

A series of eight alkyl bis(biguanide) analogues of alexidine, N,N''''-1,6-hexanediyl bis[N'-(2-ethylhexyl)imidodicarbonimidic diamide] (1), was prepared. Five of these analogues constituted a series isolipophilic with 1 but with varying bridge length between biguanide moieties. The compounds were evaluated in vitro for antibacterial and antiplaque properties against Streptococcus mutans, Actinomyces viscosus, and Actinomyces naesludii. One analogue, N N,''''-1,6-hexanediyl bis[N'(n-octyl)imidodicarbonimidic diamide], appeared to be more effective than either 1 or chlorhexidine against this spectrum of dental plaque forming microorganisms.

Comparison of antiplaque agents using an in vitro assay reflecting oral conditions.

An in vitro assay is described using saliva-treated bovine enamel slabs for determining the potential of chemotherapeutic agents to adsorb to tooth surfaces and act against plaque-forming bacteria. Chlorhexidine was found to inhibit the formation of in vitro plaque by Actinomyces viscosus, A naeslundii, Streptococcus mutans and S sanguis. Actinobolin was found to have marked antibacterial properties but limited adsorptive qualities.

In vitro antiplaque effects of antiseptic phenols.

Several phenols known to be antiseptics were tested in vitro for their ability to adsorb to saliva-coated enamel and subsequently inhibit plaque formation. 3,5,4'-tribromosalicylanilide was found to be effective against growth and plaque formation of A viscosus, A naeslundii, S mutans and S sanguis. Dibromsalicil was effective against A viscosus. The other phenols (hexylresorcinol, thymol, phenylphenol and zinc phenolsulfonate) did not inhibit in vitro growth or plaque formation.

Synthesis and properties of mesoionic pyrimido[1,2-b-a1pyridazine-2,4-diones and mesoionic pyridazino[2,3-a-a1-s-trizine-2,4-diones: mesoionic analogs structurally related to fervenulin.

Derivatives of two new and unusual classes of heterocycles, possessing structural similarities to the broad spectrum antibiotic fervenulin, were synthesized and examined for in vitro antimicrobial activity. Only three of 17 mesoionic pyrimido[1,2-b]pyridazine-2,4-diones exhibited evidence of antimicrobial activity while seven of eight mesoionic pyridazino[2,3-a]-s-triazine-2,4-diones were active against one or more microorganisms. Susceptibility toward attack by nucleophiles of both mesoionic pyridazino[2,3-a]-s-triazine-2,4-diones and fervenulin was observed.

Quantitative structure-activity relationships among steroids. Investigations of the use of steric parameters.

The importance of steric factors in quantitative structure-activity relationships involving steroid hormones is discussed. a variety of steric parameters, such as parachlor, molecular volume, van der Waals volume, and including difference and squared steric terms, is explored in an attempt to find preferred forms for such expressions. Improved correlations for 6-substituted 16-methylene-17alpha-acetoxy-4,6-pregnadiene-3,20-dione derivatives were found in which activity is related to pi and a squared or difference steric factor. The activity of 9alpha-substituted cortisols correlates well with sigma I and a simple steric factor, provided that the 9alpha-hydroxylated compound is excluded from the series.