Current Organic Chemistry - Volume 27, Issue 8, 2023

The broad spectrum of biological activity of 2,6-naphthyridine, one of the six structural isomers of pyridopyridine, is the main reason for the development of new compounds containing this scaffold. This review paper aims to present various methods for obtaining 2,6-naphthyridine analogues and their biological activity, which have been reported in the scientific literature. Compounds containing the 2,6-naphthyridine moiety can be isolated from plants or obtained synthetically from various substrates: pyridine derivatives, other heterocyclic derivatives, or acyclic compounds. Biological investigations have shown that these compounds exhibit various biological activity; among others, they have an effect on the central nervous system or anticancer or antimicrobial activity.

Acquired immunodeficiency syndrome (AIDS) is an ailment that is caused primarily by the Human immunodeficiency virus (HIV), which is the main agent responsible for this deadly disease. Of all the different inhibitors employed to curtail the menace caused by this deadly virus, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been cutting edge in the fight against AIDS. Over the past few years, the diaryl pyrimidine family and its derivatives have shown promising NNRTI properties attributed to their characteristic flexibility, targeting of conserved residues of reverse transcriptase, positional adaptability and, importantly, the formation of hydrogen bonds, which altogether led to the generation of secondgeneration NNRTIs. This breakthrough in the DAPY derivatives led to the development of TMC278 (rilpivirine) and TMC125 (etravirine), the two most recently approved NNRTIs by the FDA because of their low cytotoxicity, superior activities against mutant strains and WT HIV-1, excellent potency and high specificity. However, new challenges loom on the DAPY derivatives: the disappointing pharmacokinetic properties and accelerated emergence of resistance (particularly, K1013N and Y181C mutations, which are the two most important HIV-1 mutations that persist in most of the FDA-approved regimens), which implores further research to develop novel HIV-1 NNRTIs. In this review, we detail the reported different synthetic pathways for diaryl pyrimidine modification from published articles from 2010 to 2022, their biological activities, in addition to molecular docking studies and structure-activity relationships to uncover the possible molecular contributions that improved or reduced the NNRTIs properties. In a nutshell, the research findings provide valuable insights into the various modifications of the DAPY derivatives to develop novel NNRTIs.

This review describes the progress made during the last fifty years in the synthesis and chemistry of 1,2,4,3 triazaphospholes. This class of compounds has attracted tremendous homogeneous catalysis and interest in molecular materials science. These fascinating phosphorus heterocycles have conjugated π systems with high degrees of aromaticity. 1,2,4,3- Triazaphospholes can be designed through [3+2] cyclocondensation between functionalized hydrazines with phosphonoimidates that allow the incorporation of additional donor substituents into specific positions of the phosphorus heterocycle. In addition, [4+1] cyclocondensation between functionalized amidrazones and active phosphorus reagents is the most synthetically accessible method. The used strategies facilitated synthetic access to a completely new set of triazaphospholes leading to a much broader scope for potential applications. 1,2,4,3-triazaphospholes displayed reactivity towards a variety of reagents. The phosphorus is particularly prone to undergo oxidative 1,1-addition. Protic reagents such as alcohols, phenols, and amines can be added across the P=N bond of 2H-1,2,4,3-triazaphospholes to yield the dihydro-1,2,4,3-triazaphosphole derivatives. 1H- and 2H-1,2,4,3- triazaphospholes reacted with alcohols, ammonia and amines in the presence of sulfur or selenium to form dihydro- 1,2,4,3-triazaphosphole 3-chalcogenides. The appropriate difunctional reagents such as glycols, 2-azido alcohols and phenol with a heterodiene function in the ortho position reacted with 2H-1,2,4,3-triazaphospholes to yield products formed via 1,2-addition on P=N bond. Similar behavior is shown by 2-hydroxyacetophenone and 2- hydroxy-benzophenone. 2H-1,2,4,3-Triazaphospholes reacted with acetylenes to form [3+2] cycloadducts; the latter change to 1,2,3-diazaphospholes. [4+1] Cycloadditions occurred with α-diimines, azodicarboxylic esters, and 1,2-diketones; in the latter two cases, the resulting products dimerize.

The pyrazoline moiety is present in several commercialized molecules with a wide range of applications, which has established their importance in the pharmaceutical, agricultural and industrial sectors. A large number of patents have been granted on research related to pyrazolines. Due to its broad-spectrum usefulness, scientists are continuously captivated by pyrazolines and their derivatives to study their chemistry. Several synthesis strategies can prepare pyrazolines or their analogs, and the focus will always be on new greener and more economical ways for its synthesis. Among all the methods, chalcones, hydrazines, diazo compounds, and hydrazones have been most commonly applied in different reaction conditions for the synthesis of pyrazoline and its analogs synthesis. However, there are a lot of scopes for other molecules like Huisgen zwitter ions, different metal catalysts, and nitrile imine to be used as starting reagents. The presented article consists of recently reported synthetic protocols of pyrazoline and its derivatives, which will be very useful to the researchers.