Abstract
Novel antibiotic compounds have been prepared through a selective multicomponent reaction upon the known drug Trimethoprim. The Groebke-Blackburn-Bienaymé reaction involving this α-aminoazine, with a range of aldehydes and isocyanides afforded the desired adducts in one-step. The analogs display meaningful structural features of the initial drug together with relevant modifications at several points, keeping antibiotic potency and showing satisfactory antimicrobial profile (good activity levels and reduced growth rates), especially against methicillin-resistant Staphylococcus aureus. The new products may open new possibilities to fight bacterial infections.
Highlights
Trimethoprim (TMP, 1, Figure 1A) is a well-known antibiotic, present in the Model List of Essential Medicines from the World Health Organization
We planned to develop a series of TMP derivatives through the GroebkeBlackburn-Bienaymé reaction (GBBR) by interaction of the original drug (TMP, 1) with a range of aldehydes (2) and isocyanides (3), and analyse the resulting multicomponent reaction (MCR) adducts as novel antibiotics, determining their potency, and efficiency, considering their potential impact on resistant bacteria (Scheme 3)
The preparation of TMP analogs consisted in a regioselective mono-GBBR with an aldehyde/isocyanide pair, to yield derivatives 4; it is worth mentioning that a kinetic control justifies the preferential formation of the observed isomer
Summary
Trimethoprim (TMP, 1, Figure 1A) is a well-known antibiotic, present in the Model List of Essential Medicines from the World Health Organization. These N-fused bicyclic imidazo-azines represent a special class of privileged scaffold found in several bioactive compounds and commercially available drugs, such as Zolpidem, Alpidem, Necopidem, Zolimidine, Divaplon, and SCHEME 1 | TMP-GBBR derivatives and precedent modifications on the benzyl moiety.
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