Synthesis and biological evaluation of novel 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors

Abstract

The continuous emergence of drug-resistant strains of bacteria poses an urgent risk to human health and dictates the need for new antimicrobials. Along this line, we have been working on developing inhibitors of SecA, a key component of the bacterial Sec-dependent secretion machinery. Herein, we describe the synthesis and antimicrobial evaluation of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives as potential SecA inhibitors.

Design, synthesis, and biological evaluation of pyrimidine analogs as SecA inhibitors

“…1 as a lead for further optimization. [19,15] To improve the potency, we focused our attention at the linker between the biphenyl rings and the para position of the benzylthio group. Speci cally, the designed compounds were synthesized by introducing (a) linkers such as thioethers (-S-, -CH 2 -S-), an inverted alkoxy (-O-CH 2 -), an alkenyl group (-CH = CH-), an alkynyl (-C ≡ C-) group, and an amido group (-CH 2 -NH-CO-) between the two phenyl rings and (b) substituents such as -N 3 , -COOMe, -CF 3 at the para position of the benzylthioether moiety.…”

“…At present, small organic molecules that can inhibit SecA mainly include Rose Bengal, [12] bisthiouracil, [13] bistriazole [14] and their derivatives, [15] thiazolo [4,5-d]pyrimidine derivatives [16] and others. [17,18] As an extension of our earlier work, [15,19] we are working on optimizing existing SecA inhibitors of the substituted pyrimidine scaffold by exploring the chemistry space at the 2 and 4 positions of the pyrimidine core. [13] Below, we describe the results and implications in guiding future work in this area.…”

Design, Synthesis and Biological Evaluation of Pyrimidine Analogues as SecA Inhibitors

“…At present, small organic molecules that can inhibit SecA mainly include Rose Bengal, [12] bisthiouracil, [13] bistriazole [14] and their derivatives, [15] thiazolo [4,5-d]pyrimidine derivatives [16] and others. [17,18] As an extension of our earlier work, [15,19] we are working on optimizing existing SecA inhibitors of the substituted pyrimidine scaffold by exploring the chemistry space at the 2 and 4 positions of the pyrimidine core. [13] Below, we describe the results and implications in guiding future work in this area.…”

Design, Synthesis and Antibacterial Activities of Triazole-pyrimidine Derivatives as SecA Inhibitors

“…[2,11,13] Currently, small organic molecules described in the literature as SecA inhibitors mainly include Rose Bengal, [14] bisthiouracil, [15] bistriazole [16] and their derivatives, [17] thiazolo [4,5-d]pyrimidine derivatives [18] and others. [ [19][20][21][22] In order to nd new SecA inhibitors, it is worthwhile to explore the chemistry space of known inhibitor to increase structural diversity.…”