Ethambutol. Synthesis of an unsaturated analog

New Frontiers in the Therapy of Tuberculosis: Fighting with the Global Menace

“…carrier protein [104] A number of thiolactomycm analogues have been synthesized and screened against mycobacteria with varied level of potency [105][106][107] The alkyl sulfonylcarboxamides class of compounds was originally designed to inhibit Kas of mycobacteria by mim icking the putative tetrahedral transition state arising from the condensation reaction [108,109] A related compound is considered for preclimcal trials under the name FAS20013 (19) and is very effective m killing MDR-TB organisms Isoxyl/thiocarhde (20), another thiourea containing anti-TB drug, has been used clinically in the past [110][111][112] before being supplanted by better drugs. Recent studies demon strated that one of the biological targets of isoxyl is DesA3, a A9-desaturase responsible for the synthesis of oleic acid from stearoyl-CoA [113] Based on the oxidation products of isoxyl, certain compounds, like dicyclohexylcarbodumide (20a), were reported inhibiting several enzymes involved m cation transport [114] Other remotely related hydrophobic carbodiimides like this compound were reported to inhibit bacterial membrane ATPase [115] Analogues of isoxyl with a better antimycobactenal activity have also been reported [116] High-throughput screening (HTS) of a structurally diverse library of compounds showed that indole-5-amides, 4-aryIsubstituted piperazines, and various pyrazole derivatives pro vided useful core templates that display good InhA inhibition The mechanisms of action of mtroimidazole containing PA-824 (22) and OPC-67683 (22a) have not been reported [117] yet but an enzyme involved m mycolate biosynthesis at the stage of methoxy and the ketomycolic acid syntheses has been proposed as its biological target A bioreductive activa tion of the mtroimidazooxazine-bearmg PA-824 by a combi nation of the low redox potential F420-dependent glucose 6phosphate dehydrogenase and one of the previously unstud ied protein (Rv3547) acting as the electron transfer mediator has been suggested [118,119] such as (23a) [120] or unsaturated analogs [121] are effec tive inhibitors of mycobacterial growth Thus, using a mod em medicinal chemistry approach, the synthesis of chemical libraries was undertaken featuring a central 1,2-ethylenediamine component [122][123][124] Out of the more than 100,000 plus compounds prepared, the remarkable SQ 109 (23) and other an...…”