Bioorganic Studies in AIDS: Synthetic Antifungals Against Pneumocystis carinii Based on the Multivalency Concept
نویسندگان
چکیده
We report the syntheses of antifungals containing the novel pharmacophores: oxaziridines, sulfonyloxaziridines, nitrones and nitronyl nitroxides. We hypothesized that multiple copies of the pharmacophore per molecule might be a prerequisite to enhance efficacy against the opportunistic pathogen, Pneumocystis carinii. Therefore structural optimization of the leads was based on this new “multivalency” approach. All bisoxaziridines were inactive, but a trisoxaziridine caused ca. 50% reduction of the number of P. carinii tropozoites, compared to TMP-SMX, and a hexaoxaziridine at 1 μg/ml showed activity comparable to the currently used drug, TMP-SMX. Insertion of three units of the nitronyl nitroxide pharmacophore per molecule afforded an antifungal triradical with activity comparable to TMP-SMX at 1 μg/ml; at 25 μg/ml and at 10 μg/ml the triradical was better. The results lend further support to the oxidoredox pharmacophore hypothesis, and the enhancement of activities observed demonstrates the high potential and benefits of applying the concept of multivalency to drug development.
منابع مشابه
Anti-Pneumocystis carinii and antiplasmodial activities of primaquine-derived imidazolidin-4-ones.
A series of primaquine-derived imidazolidin-4-ones were screened for their in vitro activity against Pneumocystis carinii and Plasmodium falciparum W2 strain. Most compounds were active against P. carinii above 10 microg/mL and displayed slight to marked activity. The imidazolidin-4-ones most active against P. carinii were also those most active antiplasmodial agents, in the muM range. One of t...
متن کاملUse Of Razi Bovine Kidney Cell Line For Proliferation Of Pneumocystis Carinii
Background and Objective: Pneumocystis pneumonia (PCP) has been historically the most prevalent opportunisticinfection in patients infected with the human immunodeficiencyvirus. Culture of the organism has not been faced with suitable success in artificial media, while various results have been reported for cell culture media. The aim of this study was proliferation of Pneumocystis carin...
متن کاملDisseminated pneumocystis carinii infection in AIDS.
Eight patients with AIDS and Pneumocystis carinii infection were studied. Protean manifestations were a feature not untypical of disseminated pneumocystosis. Aerosolised pentamidine as prophylaxis against P carinii pneumonia was ineffective at suppressing dissemination. The knowledge that extrapulmonary infection can occur has implications for the detection and treatment of, and prophylaxis aga...
متن کاملSerum titres of Pneumocystis carinii antibody in health care workers caring for patients with AIDS.
BACKGROUND Pneumocystis carinii pneumonia was thought to occur from reactivation of latent infection, but recent studies with the polymerase chain reaction have failed to detect P carinii in normal subjects. If pneumocystis pneumonia is therefore caused by new infection the source and mode of transmission of P carinii remains unknown. METHODS Natural exposure to P carinii was detected by meas...
متن کاملGrowth of Pneumocystis Carinii in Axenic Culture
SUMMARY In this research, which was done for two years, we investigated various liquid and solid media without feeder ceells, for the ability to support growth of P. carinii. Data obtained from counting the organisms nuclei showed that, addition of Cycloheximide, penicillin, & streptomycin to neopeptoneN-Acetyle Glucoseamine (N.P.G. medium) can provides growth requirements of organism in its...
متن کامل