ABSTRACT
In order to further investigate the potential of rifamycins as antiinflammatory drugs, twenty-five semisynthetic rifamycins were tested at concentrations ranging from 10(-9) to 10(-5) M on in vitro human neutrophil functions such as locomotion, superoxide anion production, and degranulation, under different stimulatory conditions. They were also tested as antiproliferative agents on peripheral blood lymphocytes. The present semisynthetic derivatives are in general characterized by their carrying a hydrophilic substituent; they are rifamycin S or rifamycin SV derivatives carrying at C(3) either a carboxyalkyl side-chain or a glycosyl side-chain. Derivatives of the former group displayed inhibitory activities covering the whole range of activities tested, suggesting that the sum of these different effects could support their antiinflammatory activity in vivo. These derivatives, carrying a free carboxyl, are more water soluble than rifamycin SV at physiological pH, and may serve as antiinflammatory drugs for local administration, alternative to rifamycin SV, possibly giving higher efficacy and reduced side effects of pain and tissue swelling.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Neutrophils/drug effects , Neutrophils/physiology , Rifamycins/chemistry , Rifamycins/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Degranulation/drug effects , Cell Movement/drug effects , Humans , In Vitro Techniques , Respiratory Burst/drug effects , Structure-Activity Relationship , Superoxides/metabolismABSTRACT
In our study we investigated the effect of rifamycin SV, rifamycin B, rifampicin and five semisynthetic derivatives on human neutrophil functions such as locomotion, superoxide production and degranulation stimulated by specific agonists. All compounds were tested at concentrations ranging from 10(-9) to 10(-5) M. Among the newly synthesized compounds the most active we found to be the derivatives carrying an acidic substituent at C3: these significantly lowered the superoxide generation induced by PMA throughout the entire concentration range, whereas rifamycin SV, rifamycin B and rifampicin were effective only at the highest concentrations. Moreover, chemotactic movement was significantly attenuated by derivative R4, rifamycin B and rifamycin SV at high doses; granule enzyme release was unaffected by all compounds.
