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Upstream product

• 1570-45-2 isonicotinic acid ethylester 
• 343-72-6 ethyl 3-fluoroisonicotinate 
• 393-53-3 3-fluoroisonicotinic acid 

Relevant academic research and scientific papers

Reinvestigation of the structure-activity relationships of isoniazid

Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quantitative structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-positive and gram-negative bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated analysis of the structure-activity relationship of INH that we hope will serve as useful resource for the community.

3. 6 - Disubstituted [1, 2, 4] triazolo [3, 4 - b] [1, 3, 4] thiadiazole compound and use thereof

The invention discloses 3,6-disubstituted[1,2,4]triazolyl[3,4-b][1,3,4]thiadiazole compounds represented by general formula (I), and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. The compounds can be used as a transpeptidase SrtA inhibitor of Staphylococcus aureus, Bacillus pyogenes, Bacillus anthracis, Streptococcus pneumoniae and other Gram-positive bacteria, and can be used to prepare drugs for treating pathogen infection diseases with the transpeptidase SrtA of the Gram-positive bacteria, such as Staphylococcus aureus, Bacillus pyogenes, Bacillus anthracis and Streptococcus pneumoniae as target. The compounds avoid selection pressure induced drug resistance of pathogens to a certain degree, and mitigate threat of continuous drug-resistant pathogens to the health of human.

Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains

Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure–activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv?=?0.25?μg/mL; MIC-MDRTB?=?2.0?μg/mL; MIC-RDRTB?=?0.25?μg/mL; Mt SD-IC50?=?86.39?μg/mL; and 6g-3, MIC-H37Rv?=?1.0?μg/mL; MIC-MDRTB?=?4.0?μg/mL; MIC-RDRTB?=?2.0?μg/mL; Mt SD-IC50?=?73.57?μg/mL). Compounds 6c-3 and 6g-3 possessed a para-nitro phenyl at the 6 position showed low Vero and HepG2 cells toxicity, turning out to be two excellent lead candidates for preclinical trials. In addition, in vitro Mt SD inhibitory assay indicates that Mt SD is at least one of the targets for their antitubercular activity. Thus, they may turn out to be promising multidrug-resistance-reversing agents.

SAR studies on 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents

Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of one lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (1), targeting Mt SD in our previous study, an extensive SAR study for optimization of the lead compound was performed through systematic modification of the 3 and 6 positions. This study has successfully led to the discovery of two highly potent advanced leads 6d-4, 6c-4 and several other compounds with comparable potencies (6d-4, MIC-H37Rv = 0.5 μg mL-1; MIC-MDRTB = 4.0 μg mL-1; MIC-RDRTB = 0.5 μg mL-1; Mt SD-IC50 = 14.20 μg mL-1; and 6c-4, MIC-H37Rv = 0.5 μg mL-1; MIC-MDRTB = 4.0 μg mL-1; MIC-RDRTB = 1.0 μg mL-1; Mt SD-IC50 = 6.82 μg mL-1). These advanced lead compounds possess a para-halogen phenyl at the 3 position. In vitro Mt SD inhibitory assay indicates that Mt SD is the target for their antitubercular activity. Moreover, the BacT/ALERT 3D liquid culture technology and in vitro Mt SD inhibitory assay were initially applied.