Facially amphiphilic polyaryl and polyarylalkynyl polymers and oligomers and uses thereof

1. A method of treating a microbial infection in an animal in need thereof, said method comprising administering to the animal an effective amount of a pharmaceutical composition comprising an oligomer of Formula I:

R 1 —[-A 1 - s -A 2 - s -] m —R 2   (I)

or an acceptable salt or solvate thereof,

wherein:

(i) A 1 and A 2 are independently optionally substituted m-arylene or optionally substituted m-heteroarylene, wherein one of A 1 or A 2 is substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s), and the other of A 1 or A 2 is unsubstituted; or

(ii) one of A 1 or A 2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); and the other of A 1 or A 2 is the group —C≡C(CH 2 ) p C≡C—, wherein p is 0 to 8, and the —(CH 2 ) p — alkylene chain is optionally substituted with one or more amino or hydroxyl groups;

s is —C≡C—;

R 1 is

(i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -A 1 -R 1 , wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -A 1 -s-A 2 -R 1 , wherein each of A 1 and A 2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(iii) A′-s- and R 2 is -A 1 -s-A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(iv) A′-s- and R 2 is -A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) groups(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(v) R 1 and R 2 together form a single bond;

NPL is a non-polar group independently selected from —B(OR 4 ) 2 or —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4 , wherein:

R 3 , R 3′ , and R 3″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;

U NPL is absent or selected from the group consisting of O, S, —S(═O)—, —S(═O) 2 , —NR 3 —, —(C═O)—, —(C═O)—N═N—NR 3 —, —(C═O)—NR 3 —N═N—, —N═N—NR 3 —, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—R(═O) 2 O—, —R 3 O—, —R 3 S—, —S—C═N— and —(C═O)—NR 3 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;

the —(CH 2 ) pNPL — alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are independently 0 to 2;

PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5″ ) q2PL —V, wherein:

R 5 , R 5′ , and R 5″ are independently selected hydrogen, alkyl, and alkoxy;

U PL is absent or selected from the group consisting of O, S, —S(═O)—, —S(═O) 2 —, —NR 5 —, —(C═O)—, —(C═O)—N═N—NR 5 —, —(C═O)—NR 5 —N═N—, —N═N—NR 5 —, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 5 O—, —R 5 S—, —S—C═N— and —(C═O)—NR 5 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;

V is selected from the group consisting of nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl;

the —(CH 2 ) pPL — alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated;

wherein p is 0 to 8;

pPL is 0 to 8;

q1PL and q2PL are independently 0 to 2; and

m is 1 to about 25;

with the proviso that if A 1 and A 2 are thiophene, the polar (PL) group(s) cannot be 3-(propionic acid) or methoxy(diethoxy)ethyl and the non-polar (NPL) group(s) cannot be n-dodecyl;

and a pharmaceutically acceptable carrier or diluent;

wherein the microbial infection is a bacterial infection.

2. The method of claim 1 , wherein A 1 and A 2 are optionally substituted m-phenylene.

3. The method of claim 1 , wherein one of A 1 or A 2 is substituted with one or more polar (PL) group(s) and one or more non-polar (NPL) group(s) and the other of A 1 or A 2 is unsubstituted.

4. The method of claim 1 , wherein one of A 1 or A 2 is substituted with one or more polar (PL) group(s) and the other of A 1 or A 2 is unsubstituted.

5. The method of claim 1 , wherein R 1 is

(i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -A 1 -R 1 , wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (FL) group(s) and one or more non-polar (NPL) group(s); or

(ii) A′-s- and R 2 is -A 1 -s-A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s).

6. The method of claim 5 , wherein R 1 is hydrogen or a polar group (PL), and R 2 is -A 1 -R 1 , where A 1 is optionally substituted with one or more polar (PL) group(s).

7. The method of claim 1 , wherein q1NPL, q2NPL, q1PL, and q2PL are independently 0 or 1.

8. The method of claim 7 , wherein each of q1NPL, q2NPL, q1PL, and q2PL is 0.

9. The method of claim 1 , wherein NPL is —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4 , and R 3 , R 3′ , R 3″ , R 4 , U NPL , pNPL, q1NPL and q2NPL are as defined in claim 1 .

10. The method of claim 1 , wherein R 3 , R 3 ′, and R 3 ″ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy.

11. The method of claim 1 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 -C 18 branched alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and heteroaryl, any of which is optionally substituted with one or more C 1 -C 6 alkyl or halo groups.

12. The method of claim 1 , wherein U NPL is O, S, —S(═O)—, —S(═O) 2 —, —NH—, —(C═O)—, —(C═O)—N═N—NH—, —(C═O)—NH—N═N—,—N═N—NH—, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 3 O—, —R 3 S—, —S—C═N— or —(C═O)—NR 3 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations.

13. The method of claim 12 , wherein U NPL is O, —NH—, —(C═O)—, —(C═O)—N═N—NH—, —(C═O)—NH—N═N—, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, or —R 3 O—.

14. The method of claim 1 , wherein PL is —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5″ ) q2PL —V, and R 5 , R 5′ , R 5″ , V, U PL , pPL, q1PL and q2PL are as defined above in claim 1 .

15. The method of claim 1 , wherein R 5 , R 5 , and R 5 ″ are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.

16. The method of claim 15 , wherein each of R 5 , R 5 ′, and R 5 ″ is hydrogen.

17. The method of claim 1 , wherein , wherein U PL is O, S, —S(═O)—, —S(═O) 2 —, —NH—, —(C═O)—, —(C═O)—N═N—NH—, —(C═O)—NH—N═N—,—N═N—NH—, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 5 O—, —R 5 S—, —S—C═N— or —(C═O)—NR 5 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations.

18. The method of claim 17 , wherein U PL is O, —NH—, —(C═O)—, —(C═O)—N═N—NH—, —(C═O)—NH—N═N—, —N═N—NH—, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—, —C(═O)O—, or —R 5 O—.

19. The method of claim 1 , wherein V is selected from the group consisting of amino, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, and semicarbazone, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl.

20. The method of claim 19 , wherein heteroaryl is selected from the group consisting of 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadizaole, 3-amino-1,2,4-oxadizaole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, and 2-aminopyridine.

21. The method of claim 1 , wherein pPL and pNPL are independently 0 to 4.

22. The method of claim 1 , wherein m is 1 to about 10.

23. The method of claim 1 , wherein m is 1 to about 5.

24. The method of claim 23 , wherein m is 1, 2 or 3.

25. The method of claim 1 , wherein:

A 1 and A 2 are independently optionally substituted m-phenylene, wherein

(i) one of A 1 or A 2 is substituted with one or more polar (PL) group(s) and one or more nonpolar (NPL) group(s), and the other of A 1 or A 2 is unsubstituted; or

(ii) one of A 1 or A 2 is substituted with one or more polar (PL) group(s) and the other of A 1 or A 2 is unsubstituted;

R 1 is

(i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -A 1 -R 1 , wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(ii) A′-s- and R 2 is -A 1 -s-A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s);

NPL is —(NR 3 ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4 , wherein

R 3 , R 3′ , and R 3″ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

R 4 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 -C 18 branched alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and heteroaryl, any of which is optionally substituted with one or more C 1 -C 6 alkyl or halo groups;

U NPL is absent or selected from the group consisting of O, S, —S(═O)—, —S(═O) 2 —, —NH—, —(C═O)—, —(C═O)—N═N—NH—, —(C═O)—NH—N═N—, —N═N—NH—, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 3 —O—, —R 3 —S—, —S—C═N— and —(C═O)—NR 3 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;

the alkylene chain —(CH 2 ) pNPL — is optionally substituted with one or more amino or hydroxyl groups;

pNPL is 0 to 6;

q1NPL and q2NPL are independently 0 or 1;

PL is halo or —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5″ ) q2PL —V, wherein:

R 5 , R 5′ , and R 5″ are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

U PL is absent or selected from the group consisting of O, S, —S(═O)—, —S(═O) 2 —, —NH—, —(C═O)—, —(C═O)—N═N—NH—,—(C═O)—NH—N═N—, —N═N—NH—, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—,—C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 5 O—, —R 5 S—, —S—C═N— and —(C═O)—NR 5 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;

V is selected from the group consisting of nitro, cyano, amino, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, C 6 -C 10 aryl, heterocycle, and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, lower acylamino, or benzyloxycarbonyl;

the alkylene chain —(CH 2 ) pPL — is optionally substituted with one or more amino or hydroxyl groups;

wherein p is 0 to 8;

pPL is 0 to 6;

q1PL and q2PL are independently 0 or 1; and

m is 1 to about 5.

26. A method of killing or inhibiting the growth of a microorganism, said method comprising contacting the microorganism with an effective amount of an oligomer of Formula I:

R 1 —[-A 1 - s -A 2 - s -] m —R 2   (I)

or an acceptable salt or solvate thereof,

wherein:

(i) A 1 and A 2 are independently optionally substituted arylene or optionally substituted m-heteroarylene, wherein A 1 and A 2 is substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s), and the other of A 1 or A 2 is substituted ; or

(ii) one of A 1 or A 2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); and the other of A 1 or A 2 is the group —C≡C(CH 2 ) p C≡C—, wherein p is 0 to 8, and the —(CH 2 ) p — alkylene chain is optionally substituted with one or more amino or hydroxyl groups;

s is —C≡C—;

R 1 is

(i) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -A 1 -R 1 , wherein A 1 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(ii) hydrogen, a polar group (PL), or a non-polar group (NPL), and R 2 is -A 1 -s-A 2 -R 1 , wherein each of A 1 and A 2 is as defined above and is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(iii) A′-s- and R 2 is -A 1 -s-A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) group(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(iv) A′-s- and R 2 is -A′, wherein A′ is aryl or heteroaryl, either of which is optionally substituted with one or more polar (PL) group(s), one or more non-polar (NPL) groups(s), or a combination of one or more polar (PL) group(s) and one or more non-polar (NPL) group(s); or

(v) R 1 and R 2 together form a single bond;

NPL is a non-polar group independently selected from —B(OR 4 ) 2 or —(NR 3′ ) q1NPL —U NPL —(CH 2 ) pNPL —(NR 3″ ) q2NPL —R 4 , wherein:

R 3 , R 3′ , and R 3″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one or more alkyl or halo groups;

U NPL is absent or selected from the group consisting of O, S, —S(═O)—, —S(═O) 2 —, —NR 3 —, —(C═O)—, —(C═O)—N═N—NR 3 —, —(C═O)—NR 3 —N═N—, —N═N—NR 3 —, —C(═N—N(R 3 ) 2 )—, —C(═NR 3 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 3 O—, —R 3 S—, —S—C═N— and —(C═O)—NR 3 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;

the —(CH 2 ) pNPL — alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated;

pNPL is 0 to 8;

q1NPL and q2NPL are independently 0 to 2;

PL is a polar group selected from the group consisting of halo, hydroxyethoxymethyl, methoxyethoxymethyl, polyoxyethylene, and —(NR 5′ ) q1PL —U PL —(CH 2 ) pPL —(NR 5″ ) q2PL —V, wherein:

R 5 , R 5′ , and R 5″ are independently selected from the group consisting of hydrogen, alkyl, and alkoxy;

U PL is absent or selected from the group consisting of O, S, —S(═O)—, —S(═O) 2 —, —NR 5 —, —(C═O)—, —(C═O)—N═N—NR 5 —, —(C═O)—NR 5 —N═N—, —N═N—NR 5 —, —C(═N—N(R 5 ) 2 )—, —C(═NR 5 )—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O) 2 O—, —R 5 O—, —R 5 S—, —S—C═N— and —(C═O)—NR 5 —O—, wherein groups with two chemically nonequivalent termini can adopt both possible orientations;

V is selected from the group consisting of nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , diazamino, amidino, guanidino, guanyl, semicarbazone, aryl, heterocycle and heteroaryl, any of which is optionally substituted with one or more of amino, halo, cyano, nitro, hydroxyl, —NH(CH 2 ) p NH 2 , —N(CH 2 CH 2 NH 2 ) 2 , amidino, guanidino, guanyl, aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or benzyloxycarbonyl;

the —(CH 2 ) pPL — alkylene chain is optionally substituted with one or more amino or hydroxyl groups, or the alkylene chain is unsaturated;

wherein p is 0 to 8;

p1PL is 0 to 8;

q1PL and q2PL are independently 0 to 2; and

m is 1 to about 500;

with the proviso that if A 1 and A 2 are thiophene, the polar (PL) group(s) cannot be 3-(propionic acid) or methoxy(diethoxy)ethyl and the non-polar (NPL) group(s) cannot be n-dodecyl.

wherein the microorganism is a bacterial cell.