INHIBITING DIHYDROFOLATE REDUCTASE IN A MICROORGANISM
The present invention can inhibit dihydrofolate reductase in a microorganism. In some aspects, it may also suppress pigment formation in gram negative bacteria. The suppression of pigment formation can also mediate virulence suppression on other Gram negative bacteria. As such, the compounds may be used for microbial infections. The compounds can potentiate the effects of one or more antimicrobial agents when co-administered. Compositions including the compounds are provided. The composition can further include at least one antibiotic.
1 . A composition for inhibiting dihydrofolate reductase in a microorganism including a compound represented by Formula I
wherein X and Y are independently O, S, or NR 10;
wherein Z is O, S, CR 11 R 12, or NR 13;
wherein R 1, R 2, R 9, R 10, R 11, R 12, R 13, and R 15, are independently absent, hydrogen, —C(O)R 18, —C(W)NRi 9 R 20, or substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aroxy, arylalkyl, heteroalkyl, alkylaryl, halogen, alkylheteroaryl, —NR 16 R 17;
wherein R 14 is independently absent, —C(W)NR 19 R 20, or substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aroxy, arylalkyl, heteroalkyl, alkylaryl, halogen, alkylheteroaryl, —NR 16 R 17;
wherein R 16 and R 17 are independently hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyl, alkylaryl, or alkylheteroaryl;
wherein R 18 is hydrogen, hydroxyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, aroxy, heteroaryl, arylalkyl, heteroalkyl, alkylaryl, or alkylheteroaryl;
wherein W is O, S, or NR 21;
wherein R 19, R 20, and R 21 are independently hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, heteroalkyl, alkylaryl, or alkylheteroaryl;
wherein A is a double bond or single bond; and
wherein R 15 is absent when A is a double bond,
2 . The composition of claim 1 , wherein the compound is
wherein R 1 is —O—R 4, —NR 5 R 8, or —CH 2 —R 5; R 2 is halogen, absent, —O—CH 3, or —O—CH 2 —CH 3 ; R 9 is —COOH, —CH 2 —COOH, —CH 2 —O—CH 3, or —CH 2 —CH 2 —O—CH 3; R 4 is —CH 2 —R 5 or —CO—R 5; R 5 is
R 6 is a halogen or absent; and R 7 is halogen or absent.
3 . The composition of claim 2 , wherein R 1 is at a position selected from the group consisting of 2, 3, 4, 5, and 6; R 6 is at position 4; R 7 is at position 2 or 6 and R 2 is at position 3, 4, or 5.
4 . The composition of claim 2 wherein the compound is
wherein R 1 is —O—R 4, —NR 5 R 8, or —CH 2 —R 5; R 2 is halogen, absent, —O—CH 3, or —O—CH 2 —CH 3 ; R 3 is —COOH or —CH 2 —COOH; R 4 is —CH 2 —R 5 or —CO—R 5; R 5 is
R 6 is halogen or absent; and R 7 is halogen or absent.
5 . The composition of claim 4 , wherein R 1 is at a position selected from the group consisting of 2, 3, 4, 5, and 6; R 6 is at position 4; R 7 is at position 2 or 6; and R 2 is at position 3, 4, or 5.
6 . The composition of claim 1 , wherein the compound is selected from the group consisting of compounds 2 - 4 , 6 - 7 , 10 , 13 , 15 , 17 - 20 , 22 , 24 - 25 , 27 - 31 , 34 - 37 , 42 , 44 , 48 - 50 , 52 - 53 , 56 , 60 , 62 - 63 , 69 , 80 - 82 , and 87 .
7 . The composition of claim 6 , further comprising an antibiotic.
8 . The composition of claim 7 , wherein the antibiotic is selected from the group consisting of gentamicin, amikacin, kanamycin, neomycin, spectinomycin, neamine and combinations thereof.