Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM)

• Published in: Bioorganic chemistry Vol. 91; p. 103155
• Main Authors: Reddy, Gangireddy Sujeevan, Snehalatha, Ampalam Venkata, Edwin, Rebecca Kristina, Hossain, Kazi Amirul, Giliyaru, Varadaraj Bhat, Hariharapura, Raghu Chandrashekhar, Gautham Shenoy, G., Misra, Parimal, Pal, Manojit
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.10.2019; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Chorismate mutase; Indole; Life Sciences & Biomedicine; Palladium; Physical Sciences; Pyrazole; Science & Technology; Triazinone; Triazinone; Palladium; Chorismate mutase; Indole; Pyrazole; PROTEIN; DOCKING; INDOLES; 1,2,3-BENZOTRIAZIN-4-ONE DERIVATIVES; NEMATOCIDAL ACTIVITIES; 2-ARYL; RV1885C; 1-ALKYNES; 2-HETEROARYL
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103155

Design, synthesis and evaluation of 3-indolylmethyl substituted fused triazinone derivatives were undertaken to identify potent inhibitors of chorismate mutase. [Display omitted] •3-Indolylmethyl substituted fused triazinones were explored as inhibitors of CM.•Their synthesis involved coupling-cyclization under Pd/Cu-catalysis.•Altogether 21 novel compounds were preapred in good yields.•Several compound showed significant inhibition of CM in vitro.•3d and 4d were potent (IC50 ∼ 0.4–0.9 µM) and non-toxic (till 30 µM in vitro). The chorismate mutase (CM) is considered as an attractive target for the identification of potential antitubercular agents due to its absence in animals but not in bacteria. A series of 3-indolylmethyl substituted pyrazolotriazinone derivatives were designed and docked into CM in silico as potential inhibitors. These compounds were efficiently synthesized using the Pd/Cu-catalyzed coupling-cyclization in a single pot involving the construction of indole ring. The methodology was later extended to the preparation of corresponding benzo analogs of pyrazolotriazinones i.e. 3-indolylmethyl substituted benzotriazinone derivatives. Several of these novel compounds showed significant inhibition of CM when tested in vitro at 30 µM. The SAR (Structure-Activity-Relationship) studies suggested that benzotriazinone moiety was more favorable over the pyrazolotriazinone ring. The two best active compounds showed IC50 ∼ 0.4–0.9 µM (better than the reference/known compounds used) and no toxicity till 30 µM in vitro.