2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 13. Some alkenyl derivatives with high in vitro activity against anaerobic organisms.

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Roth B, Tidwell MY, Ferone R, Baccanari DP, Sigel CW, DeAngelis D, Elwell LP

2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 13. Some alkenyl derivatives with high in vitro activity against anaerobic organisms.

J Med Chem. 1989 Aug;32(8):1949-58.

PubMed ID
2754716 [ View in PubMed
]
Abstract

A series of 2,4-diamino-5-(3,5-dialkenyl-4-methoxy- or -4-hydroxybenzyl)pyrimidines was prepared from [(allyloxy)benzyl]pyrimidines by Claisen rearrangements, and the resulting allyl phenols were further modified by methylation and rearrangement to 1-propenyl analogues. Analogous 3,4-dimethoxy-5-alkenyl derivatives were prepared by similar techniques. High in vitro antibacterial activity was obtained against certain anaerobic organisms, such as Bacteroides species and Fusobacterium, which was equal to or better than the control, metronidazole, in several cases. The profile was similar against Neisseria gonorrhoeae and Staphylococcus aureus. The 3,5-bis(1-propenyl)-4-methoxy derivative 8 was 1 order of magnitude more active against Escherichia coli dihydrofolate reductase than its saturated counterpart, and it was also more active than trimethoprim, 1. However, it was considerably less active in vitro against the Gram-negative organisms. The 3,4-dimethoxy-5-alkenyl, -5-alkyl, and -5-alkoxy analogues had very high broad-spectrum antibacterial activity. However, pharmacokinetic studies of four of the compounds in dogs and rats and in vivo studies with an abdominal sepsis model in rats showed no advantages over trimethoprim.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TrimethoprimDihydrofolate reductaseKi (nM)1.3N/AN/ADetails
TrimethoprimDihydrofolate reductaseKi (nM)5.1N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)500000000N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)600000000N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)45000000000N/AN/ADetails