Ines, cinnamic acid, and 2-bromobenzylbromide inside a tandem amidation and Nalkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct CH arylation to receive a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,two,1de]phenanthridin-6-one derivatives 4a in fantastic yields. Ultimately, the toxicological profile from the prepared final compounds, like their corresponding intermediates, was explored by way of in silico computational methods, whilst the acute toxicity toward zebrafish embryos (96 hpf-LC50 , 50 lethal concentration) was also determined in the present study. Keywords: pyrido[3,two,1-de]phenanthridin-6-ones; N-aryl-N-(2-bromobenzyl) cinnamamides; intramolecular Friedel-Crafts alkylation; catalyzed direct C arylation; in silico computational approaches; zebrafish embryos toxicity1.BMP-7 Protein custom synthesis Introduction The exploration and study with the synthesis of nitrogen-containing polycyclic compounds is amongst the significant difficult objectives in current organic chemistry due to the fascinating biological properties of those scaffolds [1]. For this purpose, straightforward and relevant N-heterocycles fused into a single skeleton could serve as a valuable platform for the discovery of new bioactive compounds and thereby design novel synthetic strategies for their preparation, an essential and actual activity [2]. In this sense, representative examples of your isoquinoline core, which can be the principle unit of aporphinoid alkaloids 1 [5,6] plus the phenanthridine skeleton present within the structure of lycorines 2, a group of amaryllidaceae alkaloids [7,8], have led towards the discovery of a promising antitumor, antibacterial, and antiprotozoal agent (Figure 1). Below this strategy, our research group envisioned that the combination between quinolines and isoquinolines will be a fantastic technique inside the search for biologically active nitrogen-containing polycyclic compounds, but in the exact same time, we thought of that the power of this tool might be enhanced if the proposed structures had been oxidized [9,10]. Hence, unknown nitrogen-containing tetracyclic molecules with the ring ABCD technique can be assembled in the fusion of isoquinolin-1(2H)-one and quinoline, providing theCopyright: 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is definitely an open access article distributed below the terms and conditions with the Inventive Commons Attribution (CC BY) license ( creativecommons.org/licenses/by/ four.0/).Molecules 2022, 27, 8112. doi.org/10.3390/moleculesmdpi/journal/moleculesFigure 1. Fused systems based around the isoquinoline and phenanthridine scaffolds.Molecules 2022, 27, 8112 two ofOR PEER REVIEWUnder this approach, our study group envisioned that the combin corresponding pyrido[3,two,1-de]phenanthridin-8-one 3, when the respective pyrido[3,two,1quinolines and isoquinolines will be a great approach within the look for bio de]phenanthridin-6-one 4 outcomes from the fusion of isoquinoline and quinolin-2(1H)-one skeletons (Figure two).Kallikrein-2, Human (HEK293, His) nitrogencontaining polycyclic compounds, but in the same time, we cons energy of this tool are going to be enhanced in the event the proposed structures have been oxidiz unknown nitrogencontaining tetracyclic molecules with the ring ABCD assembled from the fusion of isoquinolin1(2H)1 and quinoline, providing t ing pyrido[3,two,1de]phenanthridin8one three, though the respective pyrido[3 thridin6one four outcomes from the fusion of isoquinoline and quinolin2(1H (.PMID:24268253