Part I. Synthesis of N-substituted 2,5-bis-[4-guanidinophenyl]thiophenes as potential antileishmanial compunds. Part II. Synthesis of novel potential prodrugs of bis-guanidino and bis-amidino molecules

Leishmaniasis is a disease caused by several species of Leishmania which are associated with three clinically different manifestations of the disease: cutaneous, mucocutaneous, and visceral. The regions where leishmaniasis is endemic have expanded significantly and large population movements are fuelling a growing epidemic. More recently, co-infections of HIV and leishmaniasis are becoming more common. The interaction of the two diseases makes each more destructive, accelerating the onset of AIDS and shortening the life expectancy of HIV-infected people. Dealing with evolving infectious diseases requires development of new therapeutic agents.; Aromatic dicationic molecules have shown activity against a variety of animal models for opportunistic infections when given by intravenous infusion (e.g. Pneumocystis carinii). However, the activity of these compounds is significantly less on oral administration. With this promising background, we began to synthesize potential drugs in the guanidine family. The novel guanidino compounds have a furan or a thiophene central ring linked in a symmetrical way (positions 2 and 5) to a phenyl ring which contains the guanidino moiety. The structure of the cationic centers was modified by N-alkyl and N-aryl substitution. The new diguanidino compounds were evaluated for their activities against Leishmania and Trypanosomes. Thermal melting studies were performed to examine their binding affinity to nucleic acids by the Wilson laboratory.; Since the oral bioavailability of these dicationic potential drugs is expected to be low, a prodrug approach was used to attempt to enhance bioavailability of these type of compounds. The guanidino moiety was modified in three different ways. Single (carbamates), double (N-methoxy), and triple (a combination of carbamate and N-methoxy) potential prodrugs were synthesized. In an effort to develop new prodrugs for the amidine functional group, 4,5-dihydro-3,5-disubstituted-1,2,4-oxadiazoles analogs of furamidine were also synthesized.