100954-66-3

Upstream product

• 607-68-1 2,4-dichloroquinazoline 
• 100-51-6 benzyl alcohol 

Downstream Products

• 129663-59-8 4-(benzyloxy)-2-(4-methylpiperazin-1-yl)-quinazoline 

Relevant academic research and scientific papers

MTH1 INHIBITORS FOR TREATING DISEASE

Disclosed herein are compounds and compositions having the structure of Formula I, which are useful in the treatment of diseases, such as cancer, where inhibition of MTHl is expected to confer an advantage to a patient. Methods of inhibition of MTHl activity in a human or animal subject are also provided.

SAR refinement of antileishmanial N2,N4-disubstituted quinazoline-2,4-diamines Dedicated to the memory of Martin John Rogers for his sincere efforts to facilitate neglected disease research, particularly in the area of drug discovery and development

Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N2,N4-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N4-(furan-2-ylmethyl)-N2-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N2,N4-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N2 and N4 exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N2 or N4 generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N4-benzyl-N2-(4-chlorobenzyl)quinazoline-2,4-diamine (15) and N2-benzyl-N4-isopropylquinazoline-2,4-diamine (40) were selected for in vivo evaluation of their pharmacokinetic and antileishmanial properties. While 15 displayed a longer plasma half-life and a greater area under the curve than 40, both compounds showed low efficacy in an acute murine visceral leishmaniasis model. Although the present study did not identify new quinazoline-2,4-diamines with promising in vivo efficacy, the reduced in vitro toxicity of derivatives bearing small alkyl groups at either N2 or N4 may provide clues for the design of safe and effective antileishmanial quinazolines.

Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach

From a series of small fragments that was designed to probe the histamine H4 receptor (H4R), we previously described quinoxaline-containing fragments that were grown into high affinity H 4R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H4R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl) quinazolin-4-amine (VUF10497, 55) as potent human H4R inverse agonists (pKi ) 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H 1 receptor (H1R) and therefore represent a novel class of dual action H1R/H4R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H4R and were found to possess anti-inflammatory properties in vivo in the rat.