Bilash Kuila

Discovery of Novel and Orally Bioavailable Inhibitors of PI3 Kinase Based on Indazole Substituted Morpholino-Triazines

A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 μM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 μM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.

A facile and chemoselective synthesis of 1,4-benzodiazepin-2-ones and dienyl thiazolidin-4-ones

An efficient protocol for chemoselective synthesis of previously unknown 1,4-benzodiazepin-2-ones and dienyl thiazolidin-4-one carboxylates in excellent yields by ring transformation reactions of functionally decorated 2-azetidin-3-thiazolidin-4-ones is reported.

Synthesis and evaluation of pyrrolotriazine based molecules as PI3 kinase inhibitors

Over activation of the PI3K/Akt/mTOR pathway is found in most cancer tumor types. Controlled regulation of this pathway using PI3K inhibitors can provide therapeutic significance in cancer treatment. Herein, we report the synthesis and evaluation of pyrrolotriazine based novel small molecules as pan-PI3K inhibitors. The SAR studies based on in vitro potency along with microsomal metabolic stability screening, identified 18 as a preclinical lead found to be suitable for in vivo evaluation. The identified lead was also found to be a selective inhibitor of PI3K isoforms and mTOR when screened across a panel of 23 homologous kinases.

A facile and highly chemoselective synthesis of 1-thia-3a,6-diaza-benzo[e]azulen-3-ones by 7-exo-dig/trig halocyclizations

This manuscript describes a study on relatively unexplored halogen mediated 7-exo-dig/trig cyclization reactions of 2-(2-amino-aryl)-3-prop-2-ynyl/allyl-thiazolidin-4-ones for the formation of thiazole condensed 1,4-benzodiazepines in good yields. The reactions are facile, chemoselective and involve the use of simple substrates leading to synthesis of diversely functionalized 1,4-benzodiazepines. The synthesis of such condensed 1,4-benzodiazepines is important in terms of their usefulness as biological active agents.