Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

Abstract

Objectives(S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action.MethodsBiomimetic Pictet–Spengler or Bischler–Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds.ResultsIn this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis.ConclusionsAs the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis.

The Pictet-Spengler Reaction Updates Its Habits

“…Several substituted THIQ [27][28][29][30][31][32][33][34][35][36][37][38][39][40] and THBC have been designed, synthesized via P-S cyclization, and evaluated for their biological activities. The list comprehends aminopeptidase N (APN) inhibition [27], multidrug resistance reversal effect [28], cytotoxicity against K562 [29], nonsaccharide activators of antithrombin [31], anticoagulants [32], microtubule disruptors for antiproliferative activity [33,34], cytotoxicity against MOLT-3 [35] or HepG2 [36] cell lines, and the inhibitory activity towards cisplatin-insensitive cell line Skov3 [37] or the growth of Mycobacterium tuberculosis [39] for THIQ. For THBC, the inhibition of topoisomerase II [41], the oncogenic RASlethality [47], and the antimalarial activity of spirocyclic structures [44][45][46]56,60] were the most studied biological properties.…”

“…towards cisplatin-insensitive cell line Skov3 [37] or the growth of Mycobacterium tuberculosis [39] for THIQ. For THBC, the inhibition of topoisomerase II [41], the oncogenic RAS-lethality [47], and the antimalarial activity of spirocyclic structures [44][45][46]56,60] were the most studied biological properties.…”

“…Chiral catalysts derived from BINOL [40,44,45] and SPINOL [49] (phosphoric acids and thiourea derivatives) stand out among the usual Brønsted acids: TFA [35,42,47,57], HCl [58], 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) [59], 2,4,6-trichloro-1,3,5-triazine (TCT) [54], H 2 SO 4 [50], MeSO 3 H [52], TsOH [58], and mild catalysts, such as phosphate buffer [30,39] and microwave irradiation [61].…”

“…N-substituted aryl ethylamines 20 [27,31,35,36,39,40], allene-containing-tryptophan 21 [42], trifluoromethylated precursors 22 [55], and spirocyclic lactams embodying Trp 23 [56] were the most interesting amine substrates. Conversely, isatins 24 [44][45][46], enaminone 25 [52], (S)-2,3-O-isopropylidene-L-glyceraldehyde 26 [53], pyridoxal 27 [60], L/D-amino aldehydes 28 [57,63], and 11 C-labeled formaldehyde 29 [58] were the most notable carbonyl components (Figure 1).…”

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“…124,125 Enzymatic inhibition of MurE from M. tuberculosis was observed with the extracts from Columbian plants and chemically synthesized quinolone compounds thereby demonstrating that the ligases can serve as drug targets. [126][127][128][129] Additionally, as cell division and cell wall biogenesis are stringently controlled, co-operative processes, it is no surprise to find the mur ligase genes clustered in the division cell-wall (dcw) operon, further indicating that targeting this pathway will have knock-on effects on co-regulated pathways.…”