Examples where introduction of ferrocene has resulted in a loss or no change in activity

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The replacement of the aromatic ring in some non-steroidal anti-inflammatory agents (fenclofenac, flurbiprofen, fenbufen, tolmetin) by ferrocene did not improve anti-arthritic or platelet aggregatory activities in the resulting com-pounds.19 It was concluded that ferrocene is not an appropriate bioisostere for the phenyl or pyrrole ring. Ferrocene-containing penicillins and cephalosporins20 and ferrocene-containing rifamycins21 have been evaluated and found to be no better than the original antibiotic (amoxicillin, carbenicillin, cephalothin, rifamycin) in terms of potency and range of organisms affected. However, it should be noted that in many instances, the synthetic route may not permit a direct substitution of a phenyl or alkyl group by ferrocene. For example, the resemblance between amoxicillin and the ferrocene-amoxicillin derivative 3 is not particularly striking. Thus, a fair comparison of biological activities may not be feasible.

Amoxicillin

COO-Na+

Amoxicillin

The 2,4-diflurophenyl ring of fluconazole is replaced by a ferrocene ring in the ferrocene-fluconazole analogue 4.22 The replacement was expected to enhance the permeability of 4 into Candida (yeast) cells. In this case, a role was hypothesized for the metal ion. Reports have shown that the growth of Candida is dependent on iron: iron deprivation suppressed growth while iron overload had the opposite effect. However, fluconazole showed an increase in its candidacidal activity in the presence of an iron overload.23 This led to the hypothesis that the inclusion of iron (in the form of ferrocene) in the flucona-zole molecule might be an effective way of enhancing its activity against clinically important resistant Candida species. This was not found to be the case. When evaluated in vitro against several species, the ferrocene analogue actually promoted the growth of Candida. When given in a 1:1 combination with fluconazole, the anti-candidacidal activity of the latter was suppressed. The authors concluded that 4 gained ready access into the yeast cells (because of its increased lipophilicity), possibly interacted with the same molecular target as fluconazole (which would explain the inhibition) and may have released the metal ion (thus promoting growth of Candida).

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