Synthesis and preliminary screening of carbohydrazides and hydrazones of pyrrole derivatives as potential tuberculostatics.
Five carbohydrazides and 19 hydrazones of carboxylic acids of pyrrole were synthesized as new structural analogs of known tuberculostatics, such as isoniazid (CAS 54-85-3) and its popular hydrazones. The preliminary screening against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 microg/mL in 12B medium using a broth microdilution assay, the Microplate Alamar Blue Assay (MABA) registered higher inhibitory activity within the hydrazones series (up to 68 % inhibition) compared with that of the carbohydrazides (0-34 %). No simple relationship between the activity of a particular hydrazone and that of the parent carbohydrazide, or correlations with the structural features introduced by the carbonyl partner could be observed. So both most active hydrazones diethyl 5-(2-[(2,4-dimethyl-1H-3-pyrrolyl)carbonyl]hydrazonomethyl)-3-methyl-1H-2,4-pyrroledicarboxylate (22, 68 % inhibition) and ethyl 5-(4-chlorophenyl)-2-methyl-1-(2-2-1-(5-nitro-2-furyl)methylidene]hydrazino-2-oxoethyl)-1H-3-pyrrolecarboxylate (32, 55 %) originated from inactive carbohydrazides (1, 0 % and 7, 10 % respectively); ethyl 1-(2-2-[1-(3-ethoxy-4-hydroxyphenyl) methylidene] hydrazino-2-oxoethyl)-2-methyl-5-(4-nitrophenyl)-1H-3-pyrrolecarboxylate (30) showed 0 % inhibition, although derived from a hydrazide with 34 % activity. The condensation of six carbohydrazides with the same carbonyl reagent 5-nitrofurfural yielded hydrazones whose activity covered the wide range of 0-55 % inhibition.
Department Organic synthesis and fuels, University of Chemical Technology and Metallurgy, Sofia, Bulgaria. a.bijev@uctm.edu
Atanas
A
Bijev
D000995:Antitubercular Agents; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004353:Drug Evaluation, Preclinical; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D006834:Hydrazines; D006835:Hydrazones; D007202:Indicators and Reagents; D011758:Pyrroles; C019289:carbohydrazide