Multicomponent Reactions Upon the Known Drug Trimethoprim as a Source of Novel Antimicrobial Agents

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.

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs

“…One of our reviews presents an extensive range of research literature on the first and most recent achievements in TMP analogs as DHFR inhibitors and underlines new directions in developing and modeling DHFR inhibitors [33]. Currently, Pedrola et al [34] showed group of TMP 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 (Figure 1). The new products may open new possibilities to fight bacterial infections.…”

“…Singh et al [35] modified the antibacterial agent TMP to compounds A and B ( Figure 1) with promising anticancer applications. These two compounds had significant tumor growth inhibitory activities over 60 human tumor cell lines and exhibited appreciable interactions with DHFR [34]. Algul et al [36] have developed a new nonclassical series of propargyl-linked DHFR inhibitors.…”

Extended Multicomponent Reactions with Indole Aldehydes: Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of the Aryl Hydrocarbon Receptor

“…[29] The antibiotic trimethoprim suitably reacted likewise to give adduct 7 h (31 %). [30] Interestingly, 2,4-diaminopyrimidine adducts react smoothly in air, not requiring other oxidants, probably due to their higher electron density.…”

Extended Multicomponent Reactions with Indole Aldehydes: Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of the Aryl Hydrocarbon Receptor

“…2,4‐Diaminopyrimidine yielded the adducts 7 f (26 %) and 7 g (11 %) in a regioselective manner, following the protocol developed by the group [29] . The antibiotic trimethoprim suitably reacted likewise to give adduct 7 h (31 %) [30] . Interestingly, 2,4‐diaminopyrimidine adducts react smoothly in air, not requiring other oxidants, probably due to their higher electron density.…”