ABSTRACT
Some non-differentiation-induction benzo[a]phenothiazines and mutagenic benz[c]acridines more potently inhibited the mitogen-induced blast transformation of human-peripheral blood lymphocytes than differentiation-induction and non-mutagenic counterparts and phenothiazines. Differential absorption spectrophotometry revealed tight complex formation between these drugs and bacterial endotoxin or mitogens. All of these compounds only slightly affected antibody dependent cellular cytotoxicity and natural killer cell activity, but significantly inhibited the endotoxin-or heat-killed Staphylococcus aureus induced tumor necrosis factor production by human mononuclear cells. Pretreatment of mice with these drugs protected them from lethal E. coli infection. Quantumchemical analysis suggests a correlation between the biological activity of these compounds and some molecular orbital parameters such as the charge at C7, and the ratio of polar/total surface areas.
Subject(s)
Acridines/pharmacology , Adjuvants, Immunologic/pharmacology , Phenothiazines/pharmacology , Acridines/chemistry , Adjuvants, Immunologic/chemistry , Drug Interactions , Endotoxins/pharmacology , Escherichia coli Infections/drug therapy , Humans , Hydrogen-Ion Concentration , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/physiology , Lymphocyte Activation/drug effects , Phenothiazines/chemistry , Phytohemagglutinins/pharmacology , Quantum Theory , Software , Spectrophotometry, Ultraviolet , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Tricyclic compounds were able to inhibit the motility of Proteus vulgaris. The effectiveness of antimotility action was related to the physicochemical properties of the molecules, i.e. energy of HOMO, Log P, total surface. The antimotility action of the compounds was due to their reversible inhibition on the proton pump of the bacterium. Phosphate anion antagonized the antimotility, and potassium cation enhanced the action of phosphate anion on the antimotility effect induced by the agents. Glucose reversed the antimotility action of the compounds. Factors directly increasing the bacterial proton-motive force (PMF) could change bacterial motility and the antimotility action of the tricyclic compounds.
Subject(s)
Phenothiazines/pharmacology , Proteus vulgaris/drug effects , Hydrogen-Ion Concentration , Membrane Potentials , Movement/drug effects , Proteus vulgaris/physiologyABSTRACT
Effect of K- and L- molecular orbital regions on expression of antiplasmid and carcinogenic activity was studied with various benz[c]acridine derivatives, tricyclic compounds (acridine orange, phenothiazines) and dibenzoazepine (imipramine). Antiplasmid compounds showed the out-of-phase of molecular orbital in the L-region. On the other hand, mutagenic and carcinogenic compounds showed the out-of-phase in the L-region, and their energy was accumulated in the K-region of the molecular orbitals. The present study suggests that the molecular orbitals responsible for the expression of antiplasmid and carcinogenic effects might be basically different.
