Pd/Cu-catalyzed access to novel 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinone derivatives: their in silico / in vitro evaluation as inhibitors of chorismate mutase (CM).

Autor:	Reddy GS; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com.; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education Madhav Nagar Manipal 576 104 Karnataka India., Shukla S; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com.; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education Madhav Nagar Manipal 576 104 Karnataka India., Bhuktar H; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com.; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education Madhav Nagar Manipal 576 104 Karnataka India., Hossain KA; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com., Edwin RK; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com., Giliyaru VB; Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education Madhav Nagar Manipal 576 104 Karnataka India., Misra P; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com., Pal M; Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus Gachibowli Hyderabad 500 046 India manojitpal@rediffmail.com.
Jazyk:	angličtina
Zdroj:	RSC advances [RSC Adv] 2022 Sep 21; Vol. 12 (41), pp. 26686-26695. Date of Electronic Publication: 2022 Sep 21 (Print Publication: 2022).
DOI:	10.1039/d2ra05255e
Abstrakt:	In view of the reported chorismate mutase (CM or Mtb CM) inhibitory activities of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives the structurally similar 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinones were designed and evaluated in silico against CM. The docking of target molecules was performed at the interface site of Mtb CM (PDB: 2FP2). All the best ranked molecules participated in a strong H-bonding with the ILE67 of the B chain at the backbone position in addition to several hydrophobic/van der Waals interactions with the hydrophobic residues. Based on encouraging docking results, the one-pot synthesis of newly designed benzofuran derivatives was carried out using tandem Pd/Cu-catalyzed Sonogashira cross-coupling followed by intramolecular cyclization of 2-iodophenols with appropriate terminal alkynes. A range of novel 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinone derivatives were prepared in high (>80%) yields. Three molecules i.e. 3h, 3i and 3m that participated in good interaction with CM in silico showed encouraging (64-65%) inhibition at 30 μM in vitro . An SAR within this class of molecules suggested that the benzotriazinone series in general was better than the pyrazolotriazinone series. Based on molecular docking in silico , CM inhibition in vitro and computational ADME prediction the benzofuran derivatives 3i and 3m seemed to be of further medicinal interest in the context of discovery and development of new anti-tubercular agents. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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