Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline.

Ahmed T A Boraei,Assem Barakat,Sammer Yousuf,Ahmed A M Sarhan

doi:10.3390/molecules25030450

Abstract

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2–6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7–16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7–13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19–25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique.

Highlights

Nitrogen, oxygen, and sulfur-containing heterocycles are one of the most important compounds found in organic chemistry, as well as in the pharmaceutical industry [1,2,3,4,5,6]
A few studies have reported their use as inhibitors for metalloenzyme-including ureases [12], dizinc metallo-β-lactamase [13], the tumor necrosis factor alpha (TNF-α) converting enzyme [14], ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5) [15], dicopper
Many triazole-based indoles as a core structure are reported with pharmaceutical targets

Summary

Introduction

Nitrogen-, oxygen-, and sulfur-containing heterocycles are one of the most important compounds found in organic chemistry, as well as in the pharmaceutical industry [1,2,3,4,5,6]. 4-amino-1,2,4-triazole-3-thione-based indole scaffolds have drawn considerable attention in the chemical community, including in material science and agrochemical applications. The substituted triazoles have emerged in different pharmaceutical applications including antiproliferative [7], antiviral [8], antimalarial [9], antimicrobial [10], and anticonvulsant agents [11]. A few studies have reported their use as inhibitors for metalloenzyme-including ureases [12], dizinc metallo-β-lactamase [13], the tumor necrosis factor alpha (TNF-α) converting enzyme [14], ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5) [15], dicopper. Many triazole-based indoles as a core structure are reported with pharmaceutical targets.

Methods

Results

Conclusion