Derek Sharples

Some new 1-nitro acridine derivatives as antimicrobial agents

Abstract Some new 1-nitro acridine derivatives were prepared and characterized. These compounds were screened for evaluating their antimicrobial properties against Gram+ bacteria, Gram − bacteria, and mycobacteria as well as fungi. With reference to the results obtained, 1-nitro-4-aminoethylamine-9-alkylthioacridines must be considered as promising lead molecules.

Antimicrobial activity of 9-oxo and 9-thio acridines: Correlation with intercalation into DNA and effects on macromolecular biosynthesis

The antimicrobial activity of several new 9-acridinones and 9-thioalkylacridines towards Escherichia coli, Staphylococcus aureus, Mycobacterium smegmatis and Candida albicans was investigated. Minimal inhibitory, bactericidal and fungicidal concentrations were determined using a microplate assay which enabled inhibitory, bactericidal and fungicidal indices to be calculated. These indices facilitated structure/activity relationship studies. DNA-intercalating capability and DNA supercoiling inhibitory effects as well as inhibitory effects on macromolecular synthesis were determined. Results showed that intercalation into DNA, which is the mechanism of action usually postulated for acridines, cannot be correlated with the properties examined. However, inhibition of RNA synthesis may be involved in the antimicrobial activity of the drugs.

Structure elucidation of protriptyline photoirradiation products

Three photoirradiation products of the tricyclic antidepressant protriptyline have been isolated by preparative tlc and identified as the 10,11‐epoxide, 10‐hydroxy and 10,11‐dihydrodiol derivatives of protriptyline by tlc, uv and mass spectroscopy.

Synthesis of two novel thioacridinic derivatives and comparison of their in vitro biological activities

Two novel compounds, 3-amino-9-(diethylaminoethylthio) acridine and 9-diethylaminoethylthioacridine, were synthesized and characterized. They were shown to be cytotoxic against K562 and Raji cell lines. A concentration of 10(-5) M killed around 40% of the cells after 3 h time of incubation. Intercalation into DNA was more efficient when a protonated nitrogen was present in a side chain of the ring system. At the cytotoxic concentrations (10(-5) M, 10(-6) M), inhibition of nucleic acid synthesis in K562, Raji cell lines and human leukocytes has been shown. The results presented suggest that the cytotoxicity and the inhibition of nucleic acid synthesis of the two compounds studied are inversely related to their intercalating capability into the DNA helix.

New antiparasitic agents. III. Comparison between trypanocidal activities of some acridine derivatives against Trypanosoma cruzi in vitro.

Some acridine compounds referred to as 9-imino, 9-oxo and 9-thio derivatives were screened for activity against Trypanosoma cruzi in vitro. The results are discussed here with reference to the structure of the compounds tested. Attempts to elucidate the mode of action of active acridines are also included. The most active compounds that were tested were 9-thioacridanones and 9-thio-1,2,3,4-tetrahydroacridanones Added to this, the dialkylaminoalkylthio group seems to be the most convenient molecular moiety for trypanocidal activity in the 9-substituted acridine series.

New Antiamebic Acridines

A series of novel 9-acridanones and 9-iminoacridines has been prepared and investigated by a number of spectroscopic techniques in order to determine the nature and extent of the binding of these compounds to DNA. Results are discussed with reference to antiamebic activity in vitro.

Photoirradiation products of cyproheptadine and carbamazepine

Cyclobutyl dimer and 10,11‐epoxide photoirradiation products of cyproheptadine and carbamazepine have been isolated by preparative tlc and identified by tlc, uv, pmr and mass spectroscopy.

SYNTHESIS, TRYPANOCIDAL ACTIVITY AND DNA BINDING OF NEW BENZO[b][1,8]- NAPHTHYRIDONES DERIVATIVES

A novel set of N-alkyl naphthyridone compounds has been prepared and characterized. These compounds have been compared to analogous 9-acridinones for a possible trypanocidal activity. With reference to this, naphthyridones seem to be more promising compounds than the 9-acridinone ones. INTRODUCTION Within the scope of the search of new trypanocidal agents (1-3) we have recently prepared and tested some 1,4-dimethoxy-9-(10H)-acridinone derivatives (4). As the naphtyridine nucleus is structurally related to the acridine one, we were also interested in preparing and investigating antiparasitic activity of some new benzo [b][1,8]-5-naphthyridone derivatives, substituted similarly as acridinones already tested.

Binding of N‐phenylanthranilic acid derivatives to bovine serum albumin

f i e binding of drugs to extracellular protein, in particular, the albumin fraction of blood protein, has long been recognized as an important factor for consideration in drug design. Binding to serum albumin is known to affect the availability and level of response of certain pharmaceuticals. For example, phenylbutazone will displace warfarin bound to serum albumin in viva and drastically affect its blood level and its anticoagulant effect (Solomon 1970). Other drugs are known to bind to specific sites on human albumin (Whitehouse et a1 1971). The binding of drugs to specific sites is the result of a number of possible types of interaction, e.g. electrostatic, hydrogen bonding and hydrophobic interaction. The objectives of physicochemical studies of drug/ albumin binding is to isolate and quantitate the various contributions to binding that result from these interactions. An appropriate operational model for quantitating protein binding of drugs in terms of their physicochemical properties is the extra-thermodynamic model of Hansch & Fujita (1964). The non steroidal antiinflammatory drugs, flufenamic acid [N-(ar.a,cu,-trifluoro-m-toly1)anthranilic acid], meclofenamic acid [N-(2,6-dichloro-m-tolyl) anthranilic acid] and mefenarnic acid [N-(2,3-xylyl) anthranilic acid] have been shown to bind to human serum albumin using a circular dichroic technique (Chignelll969). The results suggested that both electrostatic and hydrophobic factors were involved in the binding of these drugs to human serum albumin. Attempts were made to determine the role of hydrophobic interactions in the binding of other N-phenyl-anthranilic acid derivatives to human serum albumin. This was done by looking at the correlation between the hexane-water partition coefficient of the N-phenylanthranilic acid and its association constant for binding to human serum albumin. Although some correlation was observed many compounds gave anomolous results. In this paper are reported the results of examining a wide range of substituted N-phenylanthranilic acids in an attempt to quantify the factors involved in the binding of the compounds to serum albumin.

The binding of the benzimidazole dye H8208 to DNA and to polyinosinic-polycytidylic acid.

The benzimidazole dye H8208 (2‐(4‐aminophenyl)‐5‐(4‐methylpiperazin‐1‐yl)benzimidazole) has been shown to intercalate into calf thymus DNA and into polyinosinic‐polycytidylic acid (a model for A conformation DNA) by a variety of spectroscopic techniques. The binding affinity of the dye was found to be similar to both nucleic acids.