Development of Synthetic Approaches Towards HIV Integrase Strand Transfer Inhibitors (INSTIs)

Abstract

A clear and precise report on synthetic methods for INSTIs and their intermediates are provided in the present work. HIV Integrase strand transfer inhibitors (INSTIs), a class of antiretroviral agents employed to treat HIV infected patients are placed as the second option of treatment after nucleosides. As INSTIs are employed as first line therapy to newly infected HIV positive individuals, thus synthetic routes must be easily accessible to the medicinal chemists towards lead optimization or process development. The current perspective elaborates synthetic routes of first to next generation INSTIs investigated in two decades of research and their development efforts. Further, drug resistance occurred by mutations against usage of INSTI drugs with respect to their generation also discussed. Later, discussion about synthetic development and investigation of next generation INSTIs against drug resistance HIV infections also covers to fill the gap between first/second generation INSTIs. The current perspective will draw attention of medicinal chemists and multi‐disciplinary researchers in HIV drug discovery.

A Practical Approach to Bicyclic Carbamoyl Pyridones with Application to the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors

“…Two Mg 2+ cations serve as cognate catalytic cofactors for these enzymes [ 9 , 10 , 11 ]. Metal-chelating moieties are central components of inhibitors directed against both RNase H [ 12 , 13 ] and integrase [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Integrase strand transfer inhibitors (INSTIs) are of particular interest, with recently approved INSTIs representing some of most effective anti-AIDS drugs [ 22 ].…”

“…Evolution of the metal-chelating motifs of INSTIs has played a key role in the improvements in the therapeutic efficacy of this class of drugs [ 14 , 20 ]. Of the five currently FDA-approved INSTIs (the first-generation INSTIs Raltegravir (RAL, 1 , approved in 2007) and Elvitegravir (EVG, 2 , approved in 2012), and second generation INSTIs Dolutegravir (DTG, 3 , approved in 2013), Bictegravir (BIC, 4 , approved in 2018), and Cabotegravir (CAB, 5 , approved in 2021)) the three second-generation drugs share a common metal-chelating platform based on carbamoyl pyridone motifs (9-hydroxy-2 H -pyrido [1,2- a ]pyrazine-1,8-dione 6 and the saturated congener 9-hydroxy-3,4-dihydro-2 H -pyrido [1,2- a ]pyrazine-1,8-dione ( 7 , Figure 1 ) [ 3 , 4 , 21 , 23 ]. These three INSTIs have additional rings appended onto their carbamoyl pyridone cores.…”

Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety

“…At the same time, lack of attention in the review literature has been paid to the chemical synthesis of pyridine-containing INIs. Some information can be found in two publications [11,12]. This review is an analysis of the literature on methods for the synthesis of HIV-1 integrase inhibitors of pyridine and the fused pyridine series covering the period from 2003 to the present.…”

N-Substituted Bicyclic Carbamoyl Pyridones: Integrase Strand Transfer Inhibitors that Potently Inhibit Drug-Resistant HIV-1 Integrase Mutants

“…INSTIs are important components of cART formulations. − The first-generation INSTIs raltegravir (RAL, 1 ) and elvitegravir (EVG, 2 ) have been superseded by the second-generation INSTIs dolutegravir (DTG, 3 ), bictegravir (BIC, 4 ), and cabotegravir (CAB, 5 ) (Figure ). ,,, Treatment with the first-generation INSTIs has led to the emergence of INSTI-resistant mutant forms of IN and, although second-generation INSTIs are less susceptible to the development of resistance than first-generation INSTIs, resistance is a significant problem. ,− Causes of virological failure (VF) for INSTIs are currently an active area of investigation . Because of the emergence of resistance to the second-generation INSTIs and the potential for an increased frequency of VF associated with long-acting antiretroviral therapy (LA-ART), it is critical to develop new INSTIs that retain good antiviral efficacy against the known resistant IN mutants.…”

“… 10 − 13 The first-generation INSTIs raltegravir (RAL, 1 ) and elvitegravir (EVG, 2 ) have been superseded by the second-generation INSTIs dolutegravir (DTG, 3 ), bictegravir (BIC, 4 ), and cabotegravir (CAB, 5 ) ( Figure 1 ). 10 , 12 , 14 , 15 Treatment with the first-generation INSTIs has led to the emergence of INSTI-resistant mutant forms of IN and, although second-generation INSTIs are less susceptible to the development of resistance than first-generation INSTIs, resistance is a significant problem. 13 , 16 − 25 Causes of virological failure (VF) for INSTIs are currently an active area of investigation.…”