Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties was written by North, E. Jeffrey;Scherman, Michael S.;Bruhn, David F.;Scarborough, Jerrod S.;Maddox, Marcus M.;Jones, Victoria;Grzegorzewicz, Anna;Yang, Lei;Hess, Tamara;Morisseau, Christophe;Jackson, Mary;McNeil, Michael R.;Lee, Richard E.. And the article was included in Bioorganic & Medicinal Chemistry in 2013.Application In Synthesis of 1-Ethyl-1H-pyrazol-3-amine This article mentions the following:
Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-Ph urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the Ph substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub μg/mL min. inhibitory concentrations In the experiment, the researchers used many compounds, for example, 1-Ethyl-1H-pyrazol-3-amine (cas: 55361-49-4Application In Synthesis of 1-Ethyl-1H-pyrazol-3-amine).
1-Ethyl-1H-pyrazol-3-amine (cas: 55361-49-4) belongs to pyrazole derivatives. Pyrazole is a weak base, with pKb 11.5 (pKa of the conjugated acid 2.49 at 25 °C).Pyrazole used as a ligand to prepare organometallic compounds. The presence of both electronegative nitrogen atoms in the pyrazole ring reduces the electron density of the C3- and C5-positions leaving electron density of C4-position unaltered. Thus the C4-position is vulnerable to electrophilic attack. The C3 electrophilic-position may undergo deprotonation in the presence of a strong base leading to ring opening.Application In Synthesis of 1-Ethyl-1H-pyrazol-3-amine
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics