Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.

Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.

We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.

Demographic factors influencing consent for cadaver organ donation.

The records of all donor referrals to Groote Schuur Hospital over a 5 1/2-year period were retrospectively examined to determine which factors influenced the families' decision on organ donation. In 35% of these referrals the families were not approached for consent. The reasons for this included the potential donor being unsuitable for organ donation or not meeting all the criteria for brain death. The effects of the age, sex, race and the cause of death of the potential donor on whether the family gave consent were investigated. This study demonstrates that consent was given more readily when the potential donor was aged less than or equal to 10 years, that the sex of the potential donor appeared to have no effect on the decision by the family about organ donation, that black families gave consent for organ donation less frequently than families of other race groups and that consent was obtained more easily when death was due to suicide.

Public attitudes to organ donation in South Africa.

Public attitudes to organ donation may be influenced by cultural beliefs as well as racial prejudices and superstitions. In South Africa we are able to examine these issues from both a First- and a Third-World perspective. In this study the attitudes of 1 299 urban white, 625 rural black and 826 urban black South Africans were examined. Eighty-nine per cent of white, 84% of rural black and 76% of urban black South Africans are prepared to donate their own organs. All groups are less willing to donate the organs of close relatives (76% white, 76% rural black and 67% urban black). Most people felt that this decision should be made by the person before death. Most black people (88%) felt that the race of both donor and recipient were irrelevant. Only 23% of black people were prepared to donate their corneas, compared with the 69% and 70% willing to donate their kidneys and heart respectively.