ABSTRACT
A series of substituted phenyl analogues of 5-[[4-(4,5-dihydro-2-oxazolyl) phenoxy]alkyl]-3-methylisoxazoles has been synthesized and evaluated in vitro against several human rhinovirus (HRV) serotypes. Substituents in the 2-position greatly enhanced activity when compared to the unsubstituted compound. Many of these compounds exhibited mean MICs (MIC) against five serotypes as low as 0.40 microM. The mean MIC correlated well (r = 0.83) with the MIC80 (the concentration that inhibited 80% of the serotypes tested). A quantitative structure-activity relationship study indicated a strong dependency of MIC on lipophilicity (log P) in combination with inductive effects (sigma m) and bulk factors (MW).
Subject(s)
Antiviral Agents/chemical synthesis , Isoxazoles/chemical synthesis , Oxazoles/chemical synthesis , Rhinovirus/drug effects , Humans , Indicators and Reagents , Isoxazoles/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Species Specificity , Structure-Activity RelationshipABSTRACT
A general stereospecific synthesis of (N-methyl-2,6-methano-3-benzazocin-11 beta-yl)alkanones is described and applied to the preparation of a series of alkyl ketones wherein the alkyl group is a straight or terminally branched chain containing from one to six carbon atoms. Several compounds with methoxy groups in the aromatic ring are in the morphine range of potency; they are uniformly inactive as phenazocine antagonists. Phenolic analogues range up to 100 times as potent as morphine. Those containing five or six carbon atoms in the alkyl group exhibit phenazocine antagonist activity, in one case equivalent to naloxone. This compound (3e) is selective for phenazocine in its antagonist action.
Subject(s)
Analgesics, Opioid/chemical synthesis , Azocines/chemical synthesis , Ketones/chemical synthesis , Animals , Azocines/pharmacology , Chemical Phenomena , Chemistry , Drug Interactions , Ketones/pharmacology , Mice , Narcotic Antagonists/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A general synthesis of variously substituted 2,6-methano-3-benzazocine-11-propanols is described. Nine N-CH3 derivatives and their corresponding N-cyclopropylmethyl counterparts were prepared and studied in the mouse acetylcholine induced writhing and rat phenazocine antagonism tests. The results are compared with literature information on the bridged oripavine methanols. It is concluded that the synthetic analogues have a different structure-activity profile, in general being weak agonists but potent antagonists.
