Microbiological Evaluation of 4-substituted-imidazolidine Derivatives.

In the present studies, two series of 4-substituted-imidazolidines (IIIa-i and IIIj,k) were synthesized by reacting different tetrahydro-di-Schiff bases (IIa-i and IIj,k) with p-diethylaminobenzaldehyde/ dimethylaminobenzaldehyde. The title compounds were evaluated for their antibacterial and antifungal actions against some selected microbes. The results of microbiological evaluation revealed that two compounds, 4-(1,3-bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin-2-yl)-N,N-diethyl aniline (IIIj), 4-(1,3-bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin-2-yl)-N,N-dimethyl aniline (IIIk) were good in their antibacterial as well as antifungal actions. Minimum inhibitory concentration values (MIC) of the compounds are reported.

Synthesis, Antiinflammatory and Antimicrobial Activity of Some New 1-(3-Phenyl-3,4-Dihydro-2H-1,3-Benzoxazin-6-yl)-Ethanone Derivatives.

Synthesis of title compounds (4a-j) was carried out by following aminomethylation Mannich reaction. Test compounds were effective in inhibiting edema induced by carrageenan. The percent inhibition obseved was in the range of 25-83.3%. Compound (4c, e, h and j) were also tested for analgesic effect and showed percent protection ranging between 57-65%. All the synthesized compounds were active against E. coli and S. aureus but only compounds (4 b, c, e, i and j) were active against B. subtilis. All these compound were also found active against A. niger. Compound 4j was the most active compound with 83.3% inhibition of edema, 65.35% percent protection and inhibited all the three bacterial strains.

Antihistaminic and antiviral activities of steroids of Turbinaria conoides.

The steroids 3,6,17-trihydroxy-stigmasta-4,7,24(28)-triene (A) and 14,15,18,20-diepoxyturbinarin (B) were isolated from the cyclohexane extract of brown alga, Turbinaria conoides (J. Agardh) Kutzing, and have been reported for their antimicrobial activity by us. In this study, the isolated compounds were evaluated for comprehensive antihistaminic, antiviral and cytotoxicity screening. The antihistaminic study was performed using in vitro standard animal models. Evaluation of the potency (EC(50)), affinity (pA(2)) and the maximal response (E(max)) of the histamine alone and in the presence of the compounds were determined. Antiviral activity and cytotoxicity were performed in Crandell-Rees feline kidney (CRFK) cells by a colorimetric formazan-based MTS assay. No significant antiviral activity or cytotoxicity were observed for the compounds in the CRFK cells. Compound A inhibited the histamine-induced concentration at 20 µg mL(-1)(p < 0.05). The most significant inhibition (97%) was observed for compound B (p < 0.01) at the same concentration, which was comparable to that of the positive control chlorpheniramine maleate (10 µg mL(-1)). This potentiality suggests that 14,15,18,20-diepoxyturbinarin (B) can be developed as a new lead antihistaminic agent.

New antifungal steroids from Turbinaria conoides (J. Agardh) Kutzing.

Two new steroids 3,6,17-trihydroxy-stigmasta-4,7,24(28)-triene (1) and 14,15,18,20-diepoxyturbinarin (3), together with a known compound, fucosterol (2), were isolated from the cyclohexane extract of Turbinaria conoides. The structures were elucidated on the basis of spectroscopic evidence. The isolated compounds were screened against a panel of microorganisms. Minimum inhibitory concentrations (MICs) were determined by the standard broth dilution method. Compounds 1-3 exhibited moderate antibacterial activity against the tested bacteria and inhibited the fungal growth with MIC values ranging from 2 to 16 microg mL(-1). Compound 3 was found to be most potent against Aspergillus niger, with an MIC value of 2.0 microg mL(-1). The isolation of antifungal compounds from T. conoides is reported for the first time. These results suggested that 14,15,18,20-diepoxyturbinarin (3) could be developed as a new lead antifungal agent.

Acute toxicity study and antipyretic effect of the brown alga Turbinaria conoides (J. Agardh) Kuetz.

The active principles of brown alga, Turbinaria conoides (J.Agardh) Kuetz. (Sargassaceae) was extracted with n-hexane, cyclohexane, methanol and ethanol-water (1:1) and investigated for acute toxicity and antipyretic activity. Phytochemical analysis of the extracts revealed the presence of steroids, flavonoids and reducing sugars. Acute toxicity study was performed in Wistar rats after administration of extracts orally. No mortality was observed up to the dose of 5 g/kg for methanol and ethanol-water (1:1) extracts whereas n-hexane and cyclohexane extracts were found to be toxic at the dose levels of 1 g/kg and 2 g/kg respectively. In biochemical analysis, n-hexane, cyclohexane and ethanol-water (1:1) extracts caused a significant (P<0.01) increase in serum cholesterol, protein and alkaline phosphatase levels. In haematological studies, a significant difference was observed for cyclohexane and ethanol-water (1:1) extracts in polymorphs, lymphocytes and eosinophils when compared to the control. Antipyretic activity of extracts (100-400 mg/kg doses) was carried out on yeast-induced pyrexia in rats. Cyclohexane extract exhibited more significant antipyretic activity (P<0.01) than the other extracts at a dose of 200 mg/kg (54.43%), which was comparable to that of paracetamol at a dose of 33 mg/kg. The findings validated the use of this brown alga in traditional cure of children's fever.

2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides: synthesis, reactions and biological activity.

2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides (1-17) were prepared from 3-(4-phenoxy-benzoyl)propionic acid and aromatic aldehydes. Some of the selected butenolides were reacted with ammonia and benzylamine to give corresponding 3-arylidene-5-(4-phenoxy-phenyl)-2(3H)-pyrrolones (18-23) and 3-arylidene-5-(4-phenoxy-phenyl)-1-benzyl-2(3H)-pyrrolones (24-29) respectively, which were characterized on the basis of 1H-, 13C-NMR, Mass spectrometric data and elemental analysis results. These compounds were tested for anti-inflammatory and antimicrobial actions. The compounds, which showed significant anti-inflammatory activity, were screened for their analgesic and ulcerogenic activities. Five new compounds (5, 6, 7, 25 and 26), out of 29 showed very good anti-inflammatory activity in the carrageenan induced rat paw edema test, with significant analgesic activity in the acetic acid induced writhing test together with negligible ulcerogenic action. Antibacterial activity against Staphylococcus aureus and Escherichia coli as well as antifungal activity against Candida albicans were expressed as the corresponding minimum inhibitory concentration (MIC) values. Compound 21, 22 and 23 showed excellent activity against C. albicans with MIC-10 microg/ml. Out of the above-mentioned compounds, 22 and 23 also showed good activity against S. aureus with MIC-20 and 15 microg/ml respectively.

Synthesis, pharmacological activity and hydrolytic behavior of glyceride prodrugs of ibuprofen.

For reducing the gastrointestinal toxicity associated with ibuprofen its carboxylic group was condensed with the hydroxyl group of 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate to give the ester prodrugs 3a and 3b. The release of ibuprofen from these prodrugs has been studied at pH 3, 4, 5 and 7.4 by HPLC using methanol and 0.05% phosphoric acid (80%) (70:30) as mobile phase. The prodrugs showed insignificant hydrolysis at pH 5 compared to pH 7.4 indicating that the prodrugs do not break in stomach but release ibuprofen at pH 7.4 in adequate amounts. In vivo hydrolysis studies in rats, the peak plasma concentration of ibuprofen was attained in 1.5 h in case of ibuprofen and in 2 h in prodrugs treated animals. The plasma concentration was found to be less at all times in animals treated with ibuprofen compared to the prodrugs treated animals. The maximum anti-inflammatory activity of ibuprofen was observed at 2 h whereas prodrugs showed maximum activity at 3 h and remained practically constant upto 8 h whereas a decrease in activity was observed with free ibuprofen. Further the prodrugs showed less gastric ulcers compared to ibuprofen. An average score of 0.16, 0.45, 0.97 and 0.20, 0.76, 1.02 of ulcers was observed with 3a and 3b compared to an average score of 0.75, 1.10, and 2.97 with ibuprofen. These prodrugs also showed significant protection against acetic acid induced writhings in rats. These finding suggested that both the prodrugs are better in action as compared to the parent drug and are advantageous in having less gastrointestinal side effects.

Glyceride derivatives as potential prodrugs: synthesis, biological activity and kinetic studies of glyceride derivatives of mefenamic acid.

In order to reduce the gastrointestinal side effect, of mefenamic acid, its carboxylic group was condensed with the hydroxyl group of 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate to give 3a and 3b. These compounds were evaluated for their gastric toxicity, anti-inflammatory activity by the carageenan induced paw oedema test and analgesic activity by the acetic acid induced writhing method. The release of mefenamic acid from the esters 3a and 3b was studied at pH 3, 4, 5 and 7.4 with direct analysis by reverse phase HPLC using acetonitrile:acetate buffer (0.1 M, pH 3.5): methanol (40:25:35) at 1 mL/min. The prodrugs showed less hydrolysis at pH 5 compared to pH 7.4 indicating that the prodrugs do not dissociate at stomach pH but release mefenamic acid at pH 7.4 in adequate amounts. The hydrolysis studies were also performed in rat plasma. A higher plasma concentration of mefenamic acid was observed in animals treated with 3a and 3b compared to the animals treated with the parent drug, and even after 8 h the concentration of mefenamic acid was 2 times higher. The peak plasma concentration of mefenamic acid in animals treated with mefenamic acid was attained in 1.5 h compared with 2 h in the case of prodrugs treated animals. The prodrugs showed less gastric ulceration compared to mefenamic acid at 100 mg/kg, a severity index of 1.10, 1.22 being observed with 3a, 3b and with mefenamic acid a severity index of 2.37 was observed. The prodrugs showed better anti-inflammatory activity compared to the parent drug and analgesic activity comparable to the parent drug. These findings suggest that the prodrugs 3a and 3b synthesized might be used as biolabile prodrugs of mefenamic acid with increased bioavailability and less gastrointestinal side effects.

Synthesis, biological evaluation and kinetic studies of glyceride prodrugs of diclofenac.

The prodrugs (glyceride derivatives) 3a and 3b of diclofenac were prepared by reacting 1, 2, 3-trihydroxy propane-1,3-dipalmitate/stearate with the acid chloride of diclofenac as potential prodrugs to reduce the gastrointestinal toxicity associated with them. These prodrugs were evaluated for their ulcerogenicity, anti-inflammatory and analgesic activity. It was found that the prodrugs were significantly less irritating to the gastric mucosa as indicated by severity index of 0.86, 0.78 compared to 1.6 of diclofenac. The prodrugs 3a and 3b showed better anti-inflammatory and analgesic activity than the parent drugs. The hydrolysis of prodrugs 3a and 3b were studied at pH 3, 4, 5 and 7.4. The HPLC analysis showed that the prodrugs were resistant to hydrolysis at pH 3, 4 and 5 indicating that they did not hydrolyze in acidic environment, whereas at pH 7.4 the prodrugs readily released the parent drug in significant quantities. The plasma levels of diclofenac were also analyzed by HPLC in rats after single oral dose of the prodrugs. The results indicated that the parent drugs were readily released. The concentration of diclofenac during the study was found higher in animals treated with prodrugs 3a and 3b compared with animals treated with diclofenac. The concentration of diclofenac was found to be 38.59, 33.6 and 30.36 microg/ml in animals treated with prodrugs 3a, 3b and diclofenac respectively. In conclusion, all these studies indicated that the glyceride prodrugs of diclofenac might be considered as potential biolabile prodrugs of diclofenac.

Prodrugs and mutual prodrugs: synthesis of some new pyrazolone and oxadiazole analogues of a few non-steroidal anti-inflammatory drugs.

Naproxen, probenecid, diclofenac, ibuprofen and indomethacin were converted to hydrazide derivatives via their methyl ester by reacting with hydrazine hydrate, which were further condensed with beta-keto esters to get the pyrazolone derivatives. The hydrazide derivatives of probenecid and diclofenac were also reacted with biphenyl acetic acid while naproxen hydrazide was reacted with p-chloro benzoic acid besides biphenyl acetic acid to synthesize their oxadiazole analogues. Some selected members of the compounds prepared were screened for their anti-inflammatory and analgesic activity.

Syntheses and reactions of some new 2-arylidene-4-(biphenyl-4-yl)-but-3-en-4-olides with a study of their biological activity.

2-Arylidene-4-(biphenyl-4-yl)but-3-en-4-olides also known as 3-arylidene-5-(biphenyl-4-yl)-2(3H)-furanones were prepared from 3-(4-phenyl-benzoyl) propionic acid and aromatic aldehydes. Some of the selected butenolides were reacted with ammonia and benzylamine to give corresponding pyrrolones and N-benzylpyrrolones respectively, which were characterized on the basis of 1H NMR and MS data and elemental analysis results. These compounds were tested for anti-inflammatory and anti-microbial actions. A few compounds were found to have promising anti-inflammatory activity while a fair in number of compounds showed a good anti-fungal activity and a promising antibacterial activity against S. aureus and E. coli.

Synthesis, antiinflammatory and analgesic activity of new hexahydropyrimidine derivatives.

A number of potentially active hexahydropyrimidine derivatives of pharmaceutical interest have been synthesized. Various diSchiff's bases prepared by reacting different aromatic aldehydes with 1,3-diaminopropane were suitably reduced to give their tetrahydro derivatives which were then condensed with appropriate aldehydes to give a series of hitherto unreported hexahydropyrimidines. The resulting products were evaluated by oral route for their antiinflammatory activity. The activity of compounds 11, 23 and 4 was excellent and comparable to indomethacin. In addition to oral route of administration, the antiinflammatory activity of hexahydropyrimidine derivatives was also studied topically through transdermal gels. Compounds 11, 23, 4 and 22 produced significant inhibition in edema and showed good antiinflammatory activity comparable to diclofenac sodium gel (Relaxyl gel). All these compounds were also tested for their analgesic activity and their LD50 determined. Compounds 11, 20 and 23 showed a comparable activity with aspirin. The MTD for all the compounds was found to be > 1800 mg/kg.