Search for new pharmacophores for antimalarial activity. Part I: synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides.

A total of 80 new 2-methyl-6-ureido-4-quinolinamides were synthesized and evaluated for their antimalarial activity. Several analogs elicited the antimalarial effect at MIC of 0.25 mg/mL against the chlooquine-sensitive P. falciparum strain. The IC(50) values of the active compounds were observed to be in ng/mL range and two of the analogs have better IC(50) value than the standard chloroquine. In the in vivo assay against mdr CQ resistant P. yoelii N67/P. yoelii nigeriensis, however, none of the compound showed complete suppression of parasitemia on day 7. One of the compounds displayed significant antibacterial effect against several strains of bacteria and was many-fold better than the standard drug gentamicin.

Baylis-Hillman reaction assisted parallel synthesis of 3,5-disubstituted isoxazoles and their in vivo bioevaluation as antithrombotic agents.

The solution-phase parallel synthesis involving reactions of Baylis-Hillman products of 3-substituted-5-isoxazolecarbaldehydes with nucleophiles and their in vivo antithrombotic evaluations are described along with the results of in vitro platelet aggregation inhibition assay of a few compounds. Results of the detailed evaluation of one of the compounds as an inhibitor of platelet aggregation are also presented.

Isoxazole-based derivatives from Baylis-Hillman chemistry: assessment of preliminary hypolipidemic activity.

The synthesis of isoxazole-based derivatives utilizing Baylis-Hillman chemistry and results of their preliminary bioevaluation as hypolipidemic agents in triton model are described.

Ciprofloxacin-tinidazole combination, fluconazole- azithromicin-secnidazole-kit and doxycycline- metronidazole combination therapy in syndromic management of pelvic inflammatory disease: a prospective randomized controlled trial.

BACKGROUND: Pelvic inflammatory disease is a common problem faced by the gynecologists in there out patient department. AIM: The aim of the study was to evaluate the efficacy of three treatment combinations in the syndromic management of pelvic inflammatory disease in the out patient setting. SETTING DESIGN: In the medical college hospital patients presenting in gynecology out patient department were enrolled. MATERIAL AND METHODS: One hundred and sixty five women with diagnosis of pelvic inflammatory disease were randomized into three equal groups getting ciprofloxacin (500 mg) and tinidazole (600 mg) combination twice daily for 7 days (Group 1), a kit containing fluconazole (150 mg), azithromycin (1 gm) and secnidazole (2 mg) as one time dose (Group 2) and Doxycycline 100mg twice daily and metronidazole 200 mg thrice daily for seven days (Group 3). Severity score was determined on first visit and after 1 week and 4 weeks when patients were called for follow up. STATISTICAL ANALYSIS: Chisqare test, Krusker wallis test and Mann Whitney test. RESULTS: There was significant reduction in severity score after 1 week of treatment, which was further reduced after 4 weeks in all the three groups. Cure rate was highest in-group 1 (96%) followed by group 2 (93.5) and group 3 (91.3%) but the difference was not statistically significant. Resolution of inflammatory mass was highest in group 1. The incidence of side effects was highest and compliance was lowest in the doxycycline -metronidazole group, but the difference was not statistically significant. CONCLUSION: All the three treatment combinations were found to be equally effective in the syndromic management of pelvic inflammatory disease.

Combinatorial synthesis and biological evaluation of isoxazole-based libraries as antithrombotic agents.

The 3-substituted phenyl-5-isoxazolecarboxaldehydes have been identified as activated aldehydes for the generation of isoxazole-based combinatorial libraries on solid phase through automation. Three highly functionalized isoxazole-based libraries comprising of 32, 96 and 45 compounds each have been synthesized in parallel format using Baylis Hillman reaction, Michael addition, reductive amination and alkylation reactions. With an objective of lead generation all the three libraries were evaluated for their antithrombin activity in vivo.

Search for new chemical entities as menses inducing agents.

In continuation of an ongoing program on developing nonsteroidal pregnancy interceptives to be used as a menses regulating agent, a new class of compounds belonging to 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones series has been investigated for pregnancy interceptive activity in the hamster and rat. The compounds were administered (subcutaneous) on days 4-8 (hamster) and 5-9 (rat) post coitum (PC). The animals were laparotomized on days 12 (hamster) and 16 (rat) PC. To derive percent efficacy, the total number of implantation was divided by the number of normal and resorbed implantations. Among the 14 compounds evaluated, three were found to intercept pregnancy by 100%. Another compound was active by 75%, whereas the rest were inactive. None of the active compounds were, however, active in rat with this schedule. Results indicate that the observed species- and schedule-specific activity owes its origins to differences in the implantation physiology and early post-implantation development between the two species. The study, nevertheless, offers an insight to the new class of compounds for this activity.

Syntheses and biological evaluation of alkanediamines as antioxidant and hypolipidemic agents.

A new series of compounds belonging to N,N'- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2-5a-f) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for hypolipidemic activity.

Syntheses and biological evaluation of 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones as antioxidant and hypolipidemic agents.

A new series of compounds belonging to 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones (4-12a-e) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds, namely 5b, 5d, 6e, 8a, 8b, 10b and 11a, exhibit better antioxidant activity than probucol. Two compounds, 5d and 10b, have been evaluated in detail for antioxidant and hypolipidemic activities and show comparable activity profile to that of probucol and guggulipid. From the present study it may be postulated that the mechanism of action of these compounds could be through activation of lecithin cholesterol acyltransferase (LCAT), liver lipolytic activity, increased faecal bile acid secretion and inhibition of hepatic cholesterol biosynthesis.

IV perflubron emulsion versus autologous transfusion in severe normovolemic anemia: effects on left ventricular perfusion and function.

Intact cardiac compensatory mechanisms are necessary to maintain adequate tissue oxygenation during acute normovolemic hemodilution (ANH). Left ventricular (LV) perfusion, oxygenation and function were analyzed in an experimental whole-body model of profound ANH (Hct 9%) and effectiveness of a perfluorocarbon-based oxygen carrier in maintaining myocardial oxygenation and function was evaluated. A total of 22 anesthetized dogs were hemodiluted to Hct 20% followed by a simulated, controlled blood-loss phase in which dogs were randomized to either: (1) 1:1 exchange of lost blood with autologous red blood cells (RBC-group), (2) 1:1 exchange with a colloid (control-group) and (3) 1:1 exchange with a colloid after a single dose of 1.8 g/kg BW perflubron i.v. (PFC-group). Myocardial oxygen delivery and consumption as well as endocardial perfusion were determined using radioactive microspheres. LV myocardial contractility (LV MC) was assessed from: (1) the relationship between maximum rate of LV pressure increase (LVdp/dtmax) and LV enddiastolic volume (LVEDV) and (2) analysis of the LV endsystolic pressure volume relationship (ESPVR). LV diastolic properties were reflected by (1) minimum rate of LV pressure increase (LVdp/dtmin), (2) slope and intercept of the enddiastolic pressure-volume relationship (EDPVR) and (3) the time-constant of isovolumic LV pressure decline "tau 1/2". Full sets of LV MC data were obtained from 18 dogs (n = 6 per group). LV MC (LVdp/dtmax-LVEDV relation) increased after perflubron administration. At the lowest Hct level, all parameters reflecting LV MC as well as LVdp/dtmin were significantly higher in the PFC-group than in the control-group. After profound normovolemic hemodilution (Hct 9%) superiority of LV MC and LV diastolic properties was found, when myocardial oxygenation was supported by i.v. perflubron emulsion, a temporary O2 carrier.

Influence of chronic oestrogen treatment on the density of muscarinic cholinergic receptors and calcium channels in the rabbit uterus.

Ovariectomized rabbits were treated for 1 or 8 weeks with oestrogen and the effects on uterine weight, muscarinic receptor density and nitrendipine-binding sites on myometrial membranes were studied. The wet weight of the uterus after 1 week of oestrogen treatment increased more than tenfold and increased further by approximately 50% after 8 weeks of oestrogen treatment. The muscarinic receptor density increased significantly after 1 week of oestrogen treatment. Although there was no further increase in receptor density with continuing oestrogen treatment up to 8 weeks, the muscarinic receptor affinity increased significantly. The density of nitrendipine-binding sites increased sixfold after 1 week of oestrogen treatment and did not change thereafter. Oestrogen treatment had no influence on the affinity of nitrendipine-binding sites. The increase by oestrogen in muscarinic receptor density and in nitrendipine-binding sites as shown by the present data is consistent with the generally reported increase in agonist-induced contractile response of the myometrium following oestrogen treatment.