The synthesis and evaluation of triazolopyrimidines as anti-tubercular agents.

We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells.

One-pot high-throughput synthesis of a 160-membered library of methyl 3,5-diaryl-isoxazoline-5-carboxylate pharmacophores by a 2·2·2-component reaction.

A simple and efficient methodology has been developed for the synthesis of methyl 3,5-diaryl-isoxazoline-5-carboxylates in a high-throughput fashion. This was accomplished in one-pot by a sequence of three 2-component reactions steps (2·2·2-CR), whereby compounds were obtained in overall 30-66% isolated yields. The functional group diversity was established by synthesizing a 160-membered library.

Insertion of arynes into thioureas: a new amidine synthesis.

Arynes, generated from trimethylsilyl phenyltriflate precursors, have been found to react with thioureas via a formal π-insertion into the C═S bond. The reaction contrasts with that of ureas, which proceeds via benzyne σ-insertion into the C-N bond, and represents a new, operationally simple route to functionalized amidines.

Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence.

Understanding the basis of bacterial persistence in latent infections is critical for eradication of tuberculosis. Analysis of Mycobacterium tuberculosis mRNA expression in an in vitro model of non-replicating persistence indicated that the bacilli require electron transport chain components and ATP synthesis for survival. Additionally, low microM concentrations of aminoalkoxydiphenylmethane derivatives inhibited both the aerobic growth and survival of non-replicating, persistent M.

Discovery of 1,4-dihydroxy-2-naphthoate [corrected] prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens.

Since utilization of menaquinone in the electron transport system is a characteristic of Gram-positive organisms, the 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) inhibitors 1a and 2a act as selective antibacterial agents against organisms such as methicillin-resistant Stapylococcus aureus (MRSA), Staphylococcus epidermidis (MRSE), and Mycobacterium spp. Growth of drug-resistant Gram-positive organisms was sensitive to the MenA inhibitors, indicating that menaquinone synthesis is a valid new drug target in Gram-positive organisms.

Polymer-supported (2,6-dichloro- 4-alkoxyphenyl)(2,4-dichlorophenyl)methanol: a new linker for solid-phase organic synthesis.

An acid and base stable hydroxytetrachlorodiphenylmethyl (HTPM) linker is developed for polymer-supported organic synthesis. The linkers reported here are utilized for loading carboxylic acids, amines, alcohols, and phenols, and are stable to Brønsted and Lewis acids, Brønsted bases, and a wide variety of nucleophiles. However, the HTPM linkers can conveniently be cleaved by the solvolytic displacement reactions with 20% TFA.

Highly enantioselective copper(I)-phosphoramidite-catalysed additions of organoaluminium reagents to enones.

Simple phosphoramidite ligands afford good to excellent levels of enantioselectivity in 1,4-additions of AlR3 species to enones; sequential carboalumination-ACA cascades are possible.