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

Abstract

Human immunodeficiency virus (HIV) causes one of the most dangerous diseases-acquired immunodeficiency syndrome (AIDS). An estimated about 40 million people are currently living with HIV worldwide, most of whom are already on antiretroviral therapy. This makes the development of effective drugs to combat this virus very relevant. Currently, one of the dynamically developing areas of organic and medicinal chemistry is the synthesis and identification of new compounds capable of inhibiting HIV-1 integrase-one of the HIV enzymes. A significant number of studies on this topic are published annually. Many compounds inhibiting integrase incorporate pyridine core. Therefore, this review is an analysis of the literature on the methods for the synthesis of pyridine-containing HIV-1 integrase inhibitors since 2003 to the present.

Keywords: HIV-1 integrase; human immunodeficiency virus; inhibitors; pyridine; synthetic pathways.

Figure 1

FDA-approved HIV-1 integrase inhibitors.

Scheme 1

Synthesis of pyridoxine hydroxamic acids.

Scheme 2

Nair’s synthesis of novel HIV-1 INI 9.

Scheme 3

Synthesis of 2-hydroxy-3-pyridylacrylic acid derivatives.

Scheme 4

Preparation of pyridine-containing dual inhibitors of HIV reverse transcriptase and integrase.

Scheme 5

Synthesis of indole-pyridine hybrids as potent HIV-1 INIs.

Scheme 6

Sugiyama’s approach to novel integrase-LEDGF/p75 allosteric inhibitors.

Scheme 7

Synthetic route to pyridine-based allosteric INIs 31.

Scheme 8

Synthesis of carbamoylpyridine-4-ones—novel HIV-1 INIs.

Scheme 9

Approach to 3-hydroxypyridine-4-ones.

Scheme 10

Synthesis of 3-hydroxypyridin-4-ones 44.

Scheme 11

Original synthesis of Elvitegravir.

Scheme 12

Hu’s synthesis of pyrazolyl-4-oxo-4H-quinoline-3-carboxylic acids 54.

Scheme 13

Synthesis of 6-fluoro-4-quinolone-3-carboxylic acids as potential HIV-1 INIs.

Scheme 14

Synthesis of novel 5-R-quinolone carboxylic acids—structural analogs of Elvitegravir.

Scheme 15

Preparation of 8-hydroxyquinoline tetracyclic lactams.

Scheme 16

Synthesis of new tetrahydro-1H-[1,4]oxazino [3,2-g]quinoline derivatives.

Scheme 17

Synthesis of Ru(II) complex based on quinoline derivative as ligand—structural analog of Elvitegravir.

Scheme 18

Fandrick’s efficient multi kilogram scale synthesis of quinoline based HIV-1 INI.

Scheme 19

An approach to 4-arylquinoline derivatives 95.

Scheme 20

2-Quinolone-derived INIs.

Scheme 21

Synthesis of quinoline-based INIs bearing phosphonate groups.

Scheme 22

Synthesis of fluoroquinolone ribonucleosides 109.

Scheme 23

Polyfunctional quinaldines—potential HIV-1 INIs.

Scheme 24

Synthesis of diketo-bioisosteric analogs of Roquinimex.

Scheme 25

Wang’s synthesis of quinoline-pyrimidine hybrids 124.

Scheme 26

Synthesis of 6,7-dihydro-8H-pyrrolo[3,4-g]quinolin-8-one derivatives.

Scheme 27

The first total synthesis of lamellarin α 20-sulfate.

Scheme 28

Synthesis of quinoline containing diketo acids 148.

Scheme 29

Synthesis of N-functionalized 1,2-dihydroisoquinolines.

Scheme 30

Synthesis of 1,3-dichloroisoquinoline derivatives as potential HIV-1 inhibitors.

Scheme 31

Synthesis of 1,2,3,4-tetrahydroisoquinoline and isoquinoline derivatives.

Scheme 32

Design and synthesis of N-hydroxyisoquinoline derivatives.

Scheme 33

Synthesis of benzylideneisoquinoline-1,3(2H,4H)-diones 167.

Scheme 34

Synthesis of 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives.

Scheme 35

Divergent synthesis of Dolutegravir and Cabotegravir.

Scheme 36

Alternative approach to Dolutegravir and its sodium salt.

Scheme 37

Synthesis of novel 2-pyridinone aminal series.

Scheme 38

Synthesis of dual HIV-1 reverse transcriptase RNase H domain and integrase inhibitors.

Scheme 39

Wang’s diastereoselective synthesis of Cabotegravir.

Scheme 40

Diastereoselective synthesis of Cabotegravir.

Scheme 41

Synthesis of Cabotegravir analog 201.

Scheme 42

Practical asymmetric total synthesis of partially saturated naphthyridine 202.

Scheme 43

Preparation of bicyclic 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides.

Scheme 44

Synthesis of 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid 2,4-difluorobenzylamides 216.

Scheme 45

Synthesis of 6-substituted 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid 2,4-difluorobenzylamides 218.

Scheme 46

Synthesis of Pyrrolo[2,3-b]pyridine derivatives 219 as HIV-1 INIs.

Scheme 47

Synthesis of partially saturated 7-hydroxy-1,7-naphthyridines.

Scheme 48

A method for the synthesis of new 4-hydroxy-5-azacoumarins.

Scheme 49

Zhao’s synthesis of novel bicyclic pyrrolopyridine-triones.

Scheme 50

Synthesis of azaindole hydroxamic acids as potential HIV-1 INIs.

Scheme 51

Synthesis of hydroxynaphthyridinone derivatives 254.

Scheme 52

Synthesis of 4-aza-6-nitrobenzofuroxan 255 (A) and 5-nitro-7,8-furoxanoquinoline 258 (B).

Scheme 53

Synthesis of 1,6-naphthyridine-3-carboxylic acid 269—structural analog of Elvitegravir.

Scheme 54

Synthesis of 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidines.

Scheme 55

Synthesis of methyl-3-hydroxy-4-oxo-4H-pyrido-[1,2-a]pyrimidine-2-carboxylates 279.

Scheme 56

8-Hydroxy-1,6-naphtyridines conjugated with azoles.

Scheme 57

Synthesis of azole-containing pyrido[1,2-a]pyrimidines.