One-pot synthesis of antituberculosis compounds inspired on isoniazid. novel antimycobacterial compounds

GHIANO, D; MORBIDONI HR; BORTOLOTTI, A; RESIO BALCELLS, A; LABADIE, GR

Armação dos Búzios

Simposio; 8th Brazilian Symposium on Medicinal Chemistry; 2016

Tuberculosis (TB) remains a major infectious disease and is a great cause of death throughout theworld. The WHO estimated 9.6 million new TB cases in 2014 alone. There were 1.5 million deaths from TB including 400.000 deaths caused in HIV-positive people.1 In addition to this, multidrug-resistant tuberculosis( MOR-TB) is becoming more common. Different compounds structurally relatad to INH with antibacterial and anti-TB activity have been reported.2 (Figure 1, A·C) Inspirad on that approach  we have been working on the develop of new chemical entities structurally related to isoniazid. In particular wanted to explore new scaffolds where the secondary amino group of INH is substituted (D). Figure 1. Antitubercular INH related compounds.ResultsAggarwars group have a long history using diazo compounds as convenient reactive intermediates. In particular, their reportad procedure to prepare substituted pyrazoles by condensation oftosylhydrazine with benzaldehyde, that subsequently reacted with alkynes in basic conditions, seems very promising to our purposes.3 Based on that procedure we have been able to modify the course to avoid the tosylate alimination, allowing the anionic intermediate to produce a aza-Michel reaction on methyl propiolate. (Scheme 1) A collection of compounds were preparad using aliphatic, aromatic and iospenilic aldehyde that provided the expected product as a mixture E:Z (1 :1) that was chromatographically separable.The 30 final products were assayed on M.tuberculosis H37Rv strain with 7 analogs with MIC between 20-10 ¡.1M, 5 analogs between 10-21-lM and 3 below 2 ¡.1M. The compounds did not shown Cytotoxicity on V ero ce lis.ConclusionModifying an exciting procedure we have been able to prepare N-tosyl substituted methyl acrylates structurally related to INH. The antimycobacterial potency displayed by sorne of the analogs made them as a valuable scaffold to develop new drugs