Robert A. Coburn

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.

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-hexylbiguanidooctane), 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. Agents with lower lipophilicity were generally more active than those with higher lipophilicity. Within an isolipophilic series, activity increased as methylene bridge length increased, with a requirement for a bridge of at least six carbons for activity against most bacteria. Agents with branched terminal groups were more active than agents of the same bridge length but with unbranched terminal groups. The alkyl bisbiguanides, agents which do not contain chlorophenyl moieties, have activity against the oral flora comparable with that of chlorhexidine. Of the alkyl agents evaluated in this study, hexidecidine, hexhexidine, and alexidine offer the most promise for use in control of oral diseases.

A facile selective acylation of castanospermine

Abstract A facile selective acylation on the 6-hydroxyl group of the polyhydroxylated indolizidine alkaloid castanospermine, ( 1 ), has been achieved by the in situ use of a preformed dibutyl organotin derivative.

Quantitative Structure–Activity Relationship and Quantitative Structure–Pharmacokinetics Relationship of 1,4-Dihydropyridines and Pyridines as Multidrug Resistance Modulators

PurposeThe aim of this study was to develop quantitative structure–activity/pharmacokinetic relationships (QSAR/QSPKR) for a series of synthesized 1,4-dihydropyridines (DHPs) and pyridines as P-glycoprotein (P-gp) inhibitors.MethodsMolecular descriptors of test compounds were generated by 3D molecular modeling using SYBYL and KowWin programs. Forward inclusion coupled with multiple linear regression (MLR) was used to derive a QSAR equation for Ca2+ channel binding. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for P-gp inhibition and QSPKR models. Cross-validation using the “leave-one-out” method was performed to evaluate the predictive performance of models.ResultsFor Ca2+ channel binding, the MLR equation indicated a good correlation between observed and predicted values (R2 = 0.90), and cross-validation confirmed the predictive ability of the model (Q2 = 0.67). For P-gp reversal, the model obtained by PLS could account for most of the variation in P-gp inhibition (R2 = 0.76) with fair predictive performance (Q2 = 0.62). Nine structurally related 1,4-DHP drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R2 = 0.90), and cross-validation confirmed the prediction ability (Q2 = 0.69).ConclusionQSAR/QSPKR models were developed, and the QSAR models were capable of identifying synthesized 1,4-DHPs and pyridines with potent P-gp inhibition and reduced Ca2+ channel binding. The QSPKR models provide insight into the contribution of electronic, steric, and lipophilic factors to the clearance of DHPs.

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 preclinical development process may reduce the time and cost involved in the development of new antiplaque agents.