An Efficient Synthesis of a Hydroxyethylamine (HEA) Isostere and Its α‐Aminophosphonate and Phosphoramidate Derivatives as Potential Anti‐HIV Agents

Abstract

HIV protease is a promising drug target for AIDS therapy, and several potent HIV‐1 protease inhibitors have been reported to date. Although existing inhibitors exhibit high selectivity, they have also been associated with severe side effects and the possible emergence of therapeutic resistance. As HIV protease cleaves the peptide bond via a tetrahedral intermediate, various transition‐state models such as hydroxyethylamine (HEA) have been designed. We therefore pursued an efficient synthesis of an HEA isostere; this was performed with a novel one‐pot reduction–transimination–reduction reaction sequence as a key step. α‐Aminophosphonate and phosphoramidate derivatives of the HEA isostere were designed and synthesized, and all of the synthesized derivatives were assayed for their anti‐HIV activities against wild‐type and mutant HIV strains. Phosphoramidate derivative 15 a was found to be the most active of all synthesized compounds against the IIIB and RES056 strains. As phosphonates are known to exhibit physiological stability, good cell permeability, and other promising pharmacokinetic characteristics, our newly synthesized compounds have the potential as alternatives to existing therapeutics and diagnostics.

Novel α-Aminophosphonates and α-Aminophosphonic Acids: Synthesis, Molecular Docking and Evaluation of Antifungal Activity against Scedosporium Species

“…On the other hand, changing the 1,2,4-triazole for 6fluoro-2,4-pyrimidine and with the addition of a methyl group in the linker, voriconazole is found to have an activity level 5 times greater than its predecessor (IC 50 = 0.002 µM C. albicans) [18,19]; despite these structural modifications, it is still necessary to search for alternative drugs that have a better therapeutic effect and fewer side effects, especially against the Scedosporium genus, since it has shown great resistance to azole antifungals. Thus, there is an important need to develop pharmacological alternatives for the treatment of infections caused by these and other type of fungi [20], so a promising route is the development of novel α-aminophosphonates and α-aminophosphonic monohydrolyzed acids, since these are structural analogues of α-amino acids and there have been previous reports regarding their broad biological activity, such as antiviral [21], anticancer [22], antibacterial [23] and antifungal functions [24]. The α-aminophosphonates could be obtained by the Kabachnik-Fields reaction, which is a one-pot multicomponent reaction between an amine, an aldehyde and a phosphite; there are many reports of conventional synthetic methods and non-conventional ones, such as microwave irradiation (MW) [25], with some of them involving the use of diverse catalysts [26], but there are virtually no reports regarding the synthesis of these compounds assisted by a vortex mixer with no catalysts needed, which constitutes the proposal of the present work.…”

Recent Advances in the Synthesis of α‐Aminophosphonates: A Review

“…[9][10] They are considered as a significant class of compounds with interesting biological activities. [11][12][13][14][15] Some of the α-Aminophosphonates and their corresponding α-Aminophosphonic acids exhibit several pharmacological activities such as antibiotic, [16][17] anticancer agents, [18][19] herbicide, [20][21] pesticide, [22] enzyme inhibitors" [23][24][25] peptide mimetic, [26] antioxidant, [27] antiviral, [28] anti-thrombotic agents, [29] pharmacological agents, [30] anti-HIV agents, [31] antiinflammatory activities [32] and plant growth regulators. [33] They are also used as ligands in transition-metal catalysis and organocatalysis.…”

Ultrasound-promoted solvent-free synthesis of some new α-aminophosphonates as potential antioxidants

“…Due to their outstanding biological and physical characteristics together with their usefulness as intermediates in synthesis; AAPs have found a wide variety of applications in industry, agriculture and medicine (Moonen et al, 2004;Palacios et al, 2004;Schug and Lindner, 2005). They are discovered to be antibacterial (Subramanyam et al, 2017), antifungal (Yang et al, 2006), antiviral (Xu et al, 2006), anti-inflammatory agents (Sujatha et al, 2017), anti-HIV (Bhattacharya et al, 2012), anticancer (Bahrami et al, 2016), anti-proliferative and apoptosis inducing (Huang et al, 2016a(Huang et al, , 2016bLi et al, 2015), antitumor (Liu et al, 2017), herbicidal activity (Che et al, 2016) and insecticidal activity (Jiang et al, 2013;Liu et al, 2012). Addition of trialkyl or dialkylphosphite to imines is a successful technique to obtain them (Azizi et al, 2004;Heydari et al, 2009;Kassaee et al, 2009;Manjula et al, 2013;Yadav et al, 2001).…”