Sujata G. Dastidar

The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis

Most strains of Gram-positive and Gram-negative bacteria were inhibited by 50-100 mg/l of the anti-inflammatory agent, diclofenac sodium (Dc). In vivo test using 30 or 50 microg Dc per 20 g mouse (Swiss Albino variety) significantly (P <0.001) protected the animals when challenged with 50 MLD of a virulent Salmonella typhimurium. The anti-bacterial action of Dc was found to be due to inhibition of DNA synthesis which was demonstrated using 2 micro Ci (3H) deoxythymidine uptake.

Antibacterial Activity of Artificial Phenothiazines and Isoflavones from Plants

Significant antimicrobial action was detected in vitro and in vivo in phenothiazines that are applied to humans as neuroleptics or antihistamines. Both Gram-positive and Gram-negative bacteria were equally sensitive, with the MIC varying between 25 and 100 μg/ml with most agents. Some phenothiazines were bactericidal, while others were bacteriostatic in action. Similar activity could be observed in isoflavonones obtained from the plants Sophora spp. Trifluoperazine and methdilazine exhibited antimycobacterial properties as well, and in experimental animals the latter showed definite healing properties. Chlorpromazine and thioridazine were able to eliminate R-plasmids in drug-resistant bacteria. Artificially synthesized Benzo[α]phenothiazines could effectively suppress adenovirus oncogene expression. Phenothiazines have now been shown to inhibit efflux pumps in multidrug-resistant bacteria.

Phase transfer catalyzed synthesis of bis-quinolines: antileishmanial activity in experimental visceral leishmaniasis and in vitro antibacterial evaluation.

A one-pot synthesis of some novel bis-quinolines has been achieved under phase transfer catalyzed conditions using 8-hydroxy quinoline derivatives as substrates. The synthesized analogues were evaluated for antileishmanial activity against Leishmania donovani promastigotes and amastigotes. The entire bis-quinolines showed efficacy in both in vitro and in vivo studies. Compound 5 (1,1-bis-[(5-chloro-8-quinolyl)oxy]methane) exhibited the most significant activity. Compounds 4 (1,1-bis-[(8-quinolyl)oxy]methane) and 9 (1,5-bis-[(2-methyl-8-quinolyl)oxy]pentane) also demonstrated significant leishmanicidal efficacy against established visceral leishmaniasis in BALB/c model. Ultrastructural studies of promastigotes treated with compound 5, demonstrated membrane blebbing, chromatin condensation and vacuolization in the parasites and the flagellated parasites became round shaped after treatment. Moreover, in vitro antibacterial activity of compound 5 against several bacterial strains revealed its promising efficacy. The findings suggested that 1,1-bis-[(5-chloro-8-quinolyl)oxy]methane (5) is a bright candidate to be considered as lead compound for leishmanicidal drug.

The anti-inflammatory non-antibiotic helper compound diclofenac: an antibacterial drug target

Diclofenac sodium (Dc) was found to possess antibacterial activity against both drug-sensitive and drug-resistant clinical isolates of Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Mycobacterium spp., in addition to its potent anti-inflammatory activity. The time-kill curve study indicates that this non-steroidal drug exhibits bactericidal activity against Listeria, E. coli, and M. tuberculosis. The antibacterial activity of Dc comes, in part, from its ability to inhibit the DNA synthesis of E. coli and L. monocytogenes. Dc could protect murine listeriosis, salmonellosis, and tuberculosis at doses ranged within its maximum recommended human or non-toxic ex-vivo dose. Dc possesses anti-plasmid activity and acts as a ‘helper compound’ in synergistic combination with streptomycin against E. coli and Mycobacterium or gentamicin against Listeria. This review focuses on the possible use of Dc, a non-antibiotic helper compound, in infections and inflammatory conditions, rationalized on the basis of the activities of the compounds.

New Patentable Use of an Old Neuroleptic Compound Thioridazine to Combat Tuberculosis: A Gene Regulation Perspective

Use of the old antipsychotic phenothiazine thioridazine (THZ) for therapy of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) infection is now being seriously considered. It is reported that THZ primarily acts on enzymes involved in fatty acid metabolism and membrane proteins, particularly efflux pumps, as well as oxidoreductases and proteins involved in aerobic respiration that overlap with a number of conventional antituberculous drugs. It targets the products of the Rv3160c-Rv3161c operon, which are perhaps required for the detoxification of THZ, members of the sigma factor SigB regulon that play a crucial role in protecting the pathogen against cell envelope damage, and Rv2745c, a transcription factor that regulates ATP-dependent proteolysis. Some of these genes have been shown to be essential for the survival or persistence of Mycobacterium tuberculosis in the infected host. Since THZ targets multiple pathways, including those involved in cell wall processes and respiratory chain components, it may serve as a model for multi-target drug development, as well as constitute a highly potent addition to a combination of antituberculous drug regimens. The discussion of some of the patents relevant to thioridazine to combat tuberculosis is also included in the present manuscript.

Trifluoperazine: a broad spectrum bactericide especially active on staphylococci and vibrios

Trifluoperazine showed some significant antimicrobial activity when tested against 293 strains from two Gram-positive and eight Gram-negative genera. Minimum inhibitory concentrations of the drug were measured using an agar dilution technique. Forty six of 55 strains of Staphylococcus aureus were inhibited by 10-50 microg/ml of trifluoperazine. This drug also inhibited strains of Shigella spp., Vibrio cholerae and V. parahaemolyticus at a concentration of 10-100 microg/ml. Other bacteria including Pseudomonas spp. were moderately sensitive to trifluoperazine. In the in vivo studies this compound offered significant protection to Swiss albino mice at a concentration of 30 microg/mouse (P<0.001) when challenged with 50 median lethal dose of Salmonella typhimurium NCTC 74.

Antimycobacterial activity of methdilazine (Md), an antimicrobic phenothiazine

Methdilazine (Md) could inhibit various Mycobacterium spp. at 5–15 μg/ml concentrations in vitro as well as in vivo. When Md was tested in combination with streptomycin (Sm), rifampicin (Rf) or methyl‐DOPA (m‐D), it showed synergistic effects only with respect to methyl‐DOPA.

Antimicrobial potentiality of a new non-antibiotic : the cardiovascular drug oxyfedrine hydrochloride

Ten cardiovascular drugs, having diverse pharmacological action, were screened for possible antimicrobial property against known eight sensitive bacteria, belonging to Gram positive and Gram negative types. Although five drugs failed to show antimicrobial activity and three had moderate antimicrobial action, oxyfedrine HCl and dobutamine were seen to possess pronounced antimicrobial property. Oxyfedrine was further tested in vitro against 471 strains of bacteria from two Gram positive and fourteen Gram negative genera. The minimum inhibitory concentration (MIC) of oxyfedrine was determined by agar dilution method, which ranged from 50-200 microg/ml in most of the strains, while some strains were inhibited at even lower concentrations. In animal experiments, this compound was capable of offering significant protection to Swiss strain of white mice, challenged with 50 median lethal dose (MLD) of a virulent strain of Salmonella typhimurium at concentrations of 15, 30 and 60 microg/mouse. The in vivo results were highly significant according to chi-square test.

Antimycobacterial activity of the antiinflammatory agent diclofenac sodium, and its synergism with streptomycin

Diclofenac sodium, an antiinflammatory agent, exhibited remarkable inhibitory action against both drug sensitive and drug resistant clinical isolates of Mycobacterium tuberculosis, as well as other mycobacteria. This drug was tested in vitro against 45 different strains of mycobacteria, most of which were inhibited by the drug at 10-25 µg/ml concentration. When tested in vivo, diclofenac, injected at 10 µg/g body weight of a Swiss strain of white mice, could significantly protect them when challenged with 50 median lethal dose of M. tuberculosis H37 Rv 102. According to c2 test, the in vivo data were highly significant (p<0.01). Diclofenac was further tested for synergism with the conventional antimycobacterial drug streptomycin against M. smegmatis 798. When compared with their individual effects, synergism was found to be statistically significant (p<0.05). By the checkerboard assessment procedure, the fractional inhibitory concentration index of this combination was found to be 0.37, confirming synergism.

Thioridazine protects the mouse from a virulent infection by Salmonella enterica serovar Typhimurium 74

When administered to mice at doses of 100microg/mouse and 200microg/mouse, thioridazine (TDZ) significantly protected animals from the lethality produced by a virulent strain of Salmonella enterica serovar Typhimurium and reduced the number of bacteria retrieved from the spleen, liver and heart blood. The protection conferred by TDZ against a virulent Salmonella infection is hypothesised to be due to a reduction in the 55kDa virulence protein of the outer membrane of the organism, as this protein is almost totally absent when the organism is exposed to the phenothiazine. It is further hypothesised that the reduction in the 55kDa virulence factor renders the organism susceptible to the action of hydrolytic enzymes of the neutrophil phagolysosome, whereas in the absence of exposure to TDZ intracellular ingestion and localisation of the phagocytosed bacterium does not result in killing owing to rapid induction of the two-step PmrA/B regulon that results in the eventual synthesis and insertion of lipid A into the nascent lipopolysaccharide layer of the outer membrane.