Zhang_2021_Eur.J.Med.Chem_213_113202

Reference

Title : Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules - Zhang_2021_Eur.J.Med.Chem_213_113202
Author(s) : Zhang W , Liu LL , Lun S , Wang SS , Xiao S , Gunosewoyo H , Yang F , Tang J , Bishai WR , Yu LF
Ref : Eur Journal of Medicinal Chemistry , 213 :113202 , 2021
Abstract :

We previously reported a series of coumestans-a naturally occurring tetracyclic scaffold containing a delta-lactone-that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding 'open-form' ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra Pi-Pi stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H(37)Rv. Initial comparison of the 'open-form' analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the delta-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H(37)Rv with MIC value between 0.0313 and 0.0625 microg/mL, with high selectivity to Vero cells (64-128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria.

PubMedSearch : Zhang_2021_Eur.J.Med.Chem_213_113202
PubMedID: 33516983
Gene_locus related to this paper: myctu-PKS13

Related information

Gene_locus myctu-PKS13

Citations formats

Zhang W, Liu LL, Lun S, Wang SS, Xiao S, Gunosewoyo H, Yang F, Tang J, Bishai WR, Yu LF (2021)
Design and synthesis of mycobacterial pks13 inhibitors: Conformationally rigid tetracyclic molecules
Eur Journal of Medicinal Chemistry 213 :113202

Zhang W, Liu LL, Lun S, Wang SS, Xiao S, Gunosewoyo H, Yang F, Tang J, Bishai WR, Yu LF (2021)
Eur Journal of Medicinal Chemistry 213 :113202