Reduced toxicity molecular conjugates of anti-fungal agents
View Patent ↗Compositions, compounds and methods are described for addressing both toxicity of membrane disruptive anti-microbial agents as well as poor transport of such agents across the blood-brain-barrier (BBB) via the use of molecular appendages including one or more facial amphiphiles. These molecules have in vitro anti-fungal activity that is very similar to that of the native drug but with hemolytic activity and toxicity towards mammalian cells that is greatly reduced.
1. A compound comprising:
a polyene macrolide antibiotic; and
a single facial amphiphile bound to the polyene macrolide antibiotic via a non-cleavable linker;
wherein the facial amphiphile is sterol or amphiphilic derivative thereof; and the facial amphiphile is bound to the non-cleavable linker via an amide bond.
2. The compound of claim 1 , wherein the non-cleavable linker consists of a hydrocarbon chain.
3. The compound of claim 2 , wherein the hydrocarbon chain is a linear alkane ranging from 3 to 15 carbon groups.
4. The compound of claim 1 , wherein the non-cleavable linker consists of a polyether.
5. The compound of claim 1 , wherein the polyene macrolide antibiotic is any one of amphotericin B, nystatin, mycoheptin, candicidin, perimycin, and pimaricin, or any derivative thereof.
6. The compound of claim 1 , wherein the sterol is any one of cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, and amphiphilic derivatives thereof.
7. The compound of claim 1 , wherein the facial amphiphile has the following structure:
wherein each R is any one of H, CONH(CH 2 ) x NH 2 , CH 2 COH(CH 2 ) x OH, CH 2 OH, (CH 2 ) x OH, CH 2 COOH, (CH 2 ) x COOCH 3 , (CH 2 ) x COO(CH 2 ) y CH 3 , (CH 2 ) x CHO, (CH 2 ) x COCH 3 , (CH 2 ) x CO(CH 2 ) y CH 3 CONH(CH 2 ) x NH 3 Cl, CH 2 NH 2 , (CH 2 ) x NH 2 , (CH 2 ) x NH(CH 2 ) y NH 2 , an alkyl phosphate, an alkyl phosphate ester, an alkyl phosphonate, an alkyl sulfate, an alkyl sulfonate, a sulfone, a sulfonamide, where x and y are integers; or
wherein OR is any one of a phosphate, a phosphate ester, a phosphonate, a sulfate, a sulfonate.
8. The compound of claim 1 , wherein the facial amphiphile has the following structure:
wherein each R is any one of H, CONH(CH 2 ) x NH 2 , CH 2 COH(CH 2 ) x OH, CH 2 OH, (CH 2 ) x OH, CH 2 COOH, (CH 2 ) x COOCH 3 , (CH 2 ) x COO(CH 2 ) y CH 3 , (CH 2 ) x CHO, (CH 2 ) x COCH 3 , (CH 2 ) x CO(CH 2 ) y CH 3 CONH(CH 2 ) x NH 3 Cl, CH 2 NH 2 , (CH 2 ) x NH 2 , (CH 2 ) x NH(CH 2 ) y NH 2 , an alkyl phosphate, an alkyl phosphate ester, an alkyl phosphonate, an alkyl sulfate, an alkyl sulfonate, a sulfone, a sulfonamide, where x and y are integers; or
wherein OR is any one of a phosphate, a phosphate ester, a phosphonate, a sulfate, a sulfonate.
9. A compound comprising:
a polyene macrolide antibiotic; and
a molecular float having any one of the following chemical structures:
wherein m is an integer ranging from 1 to 8;
wherein each R is any one of H, CONH(CH 2 ) x NH 2 , CH 2 COH(CH 2 ) x OH, CH 2 OH, (CH 2 ) x OH, CH 2 COOH, (CH 2 ) x COOCH 3 , (CH 2 ) x COO(CH 2 ) y CH 3 , (CH 2 ) x CHO, (CH 2 ) x COCH 3 , (CH 2 ) x CO(CH 2 ) y CH 3 CONH(CH 2 ) x NH 3 Cl, CH 2 NH 2 , (CH 2 ) x NH 2 , (CH 2 ) x NH(CH 2 ) y NH 2 , an alkyl phosphate, an alkyl phosphate ester, an alkyl phosphonate, an alkyl sulfate, an alkyl sulfonate, a sulfone, a sulfonamide, where x and y are integers; or
wherein OR is any one of a phosphate, a phosphate ester, a phosphonate, a sulfate, a sulfonate; and
wherein m is an integer ranging from 1 to 8;
wherein each R is any one of H, CONH(CH 2 ) x NH 2 , CH 2 COH(CH 2 ) x OH, CH 2 OH, (CH 2 ) x OH, CH 2 COOH, (CH 2 ) x COOCH 3 , (CH 2 ) x COO(CH 2 ) y CH 3 , (CH 2 ) x CHO, (CH 2 ) x COCH 3 , (CH 2 ) x CO(CH 2 ) y CH 3 CONH(CH 2 ) x NH 3 Cl, CH 2 NH 2 , (CH 2 ) x NH 2 , (CH 2 ) x NH(CH 2 ) y NH 2 , an alkyl phosphate, an alkyl phosphate ester, an alkyl phosphonate, an alkyl sulfate, an alkyl sulfonate, a sulfone, a sulfonamide, where x and y are integers; or
wherein OR is any one of a phosphate, a phosphate ester, a phosphonate, a sulfate, a sulfonate.
10. The compound of claim 9 , wherein the molecular float is bound to the polyene macrolide antibiotic via an amide bond.
11. The compound of claim 9 , wherein the polyene macrolide antibiotic is any one of amphotericin B, nystatin, mycoheptin, candicidin, perimycin, and pimaricin, or any derivative thereof.