Combinatorial Lead Optimization of [1,2]-Diamines Based on Ethambutol as Potential Antituberculosis Preclinical Candidates

Abstract

Despite relatively modest potency, ethambutol (EMB, (S,S)-[N,N-di-2-amino-1-butanol]ethylenediamine) is a mainstay of contemporary chemotherapy for the treatment of tuberculosis. We have developed a solid-phase synthesis of 1,2-diamine analogues of EMB using a novel acylation-reduction sequence that is compatible with high-throughput 96-well format chemistry. Using this procedure, we have synthesized 63 238 diamine analogues in pools of 10 that are suitable for testing. MIC and a target-based reporter assay were used to direct deconvolution of 2796 individual compounds from these mixtures, and the 69 most potent molecules were resynthesized in milligram quantities for hit confirmation. Purification of these individual active diamine analogues allowed the identification of 26 compounds with activity equal to or greater than EMB. Amines which occurred most frequently in active compounds included many with large hydrophobic moieties, suggesting that optimization was perhaps selecting for the isoprenoid binding site of the arabinosyltransferase target of EMB. N-Geranyl-N'-(2-adamantyl)ethane-1,2-diamine (109), the most active of these diamines, displayed a 14-35-fold improvement in activity in vitro against Mycobacterium tuberculosis, as compared to EMB.

In vitro investigation of the antimicrobial activity of a series of lipophilic phenols and naphthols

“…The activity against Gram-positive bacteria has been reported also for the adamantyl derivatives of oxadiazoles, thioureas and thiadiazoles. 25,26,29 However, the activity data are not comparable since different activity tests were employed. 33 Adamantyl derivative of Platensimycin was found also as extremely potent against Gram-positive methicillinresistant Staphylococcus aureus (MRSA) exhibiting activity in the range 1-2 µg/mL.…”

“…21 Characterization of product 24 compares well with literature (mp = 103-105°C). 21 (25) was prepared from 24 by treatment with BBr 3 in 79 % yield according to the published procedure. 21 Characterization of product 25 compares well with literature (mp = 155-157°C).…”

“…Moreover, many of our derivatives bear an adamantyl substituent, and the antibacterial activity of a number of adamantane derivatives has been reported. [25][26][27][28][29] The in vitro antimicrobial testing was performed on five strains of microorganisms, Gram-positive Staphylococcus aureus and Bacillus subtilis, Gram-negative Escherichia coli and Klebsiella pneumoniae, and the fungus Candida albicans.…”

Chemotherapeutic Strategies and Targets Against Resistant TB

“…It was the most potent compound (MIC = 0.1-0.63 μg/mL) in the series (Lee et al, 2003). In vivo studies showed 1 to 2.0-log reduction in CFU counts in the lung and spleen at 25 mg/kg.…”

Tuberculosis: Still a Way to go ahead for a Lead- A Review

“…SQ109 hinders the action of MmpL3, an essential membrane protein which transport trehalose monomycolate into the cell envelope. So it inhibits genesis of mycolic acid of cell wall instead of inhibiting arabinosyl transferase which is the prime action ethumbutol [39][40][41][42].…”