Review
doi: 10.3390/ijms26189023.
Recent Advances in Heterocyclic HIV Protease Inhibitors
Affiliations
- PMID: 41009589
- PMCID: PMC12470081
- DOI: 10.3390/ijms26189023
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Review
Recent Advances in Heterocyclic HIV Protease Inhibitors
Int J Mol Sci.
.
Abstract
Since the first cases of AIDS, reported in 1980, this disease has become chronic over the years, and researchers have been trying to keep it under control. Despite the development and spread of mutate viruses, HIV protease remains an important pharmacological target. In the development of new HIV protease inhibitors, heterocyclic fragments have proven to be of great importance, owing to their rigid core structure, which may fit better into the enzyme's hydrophobic pockets, and the presence of a heteroatom, which may increase the number of H-bonding interactions at the active site. According to the concept of targeting the protein backbone, different aromatic or non-aromatic heterocyclic moieties have yielded inhibitors with sufficient activity against mutant viruses. This paper provides an overview of HIV protease inhibitors developed over the last fifteen years, with a focus on the presence of heterocycles in their structure, either in the core or on the side chains, which are crucial for their activity. The rationale behind the design of these new inhibitors, as well as the key synthetic steps involved in their preparation, is also described.
Keywords: AIDS; HIV-1 protease inhibitors; biological activity; heterocycles; synthesis.
Conflict of interest statement
The authors declare no conflicts of interest.
Figures
Synthesis of bis-THF-alcohol 3 by kinetic resolution of endo rac 2.
Chemoenzymatic synthesis of bis-THF-alcohol 3 from 1,2-dihydrofuran 5.
One-pot synthesis of bis-THF-alcohol 3 from 1,2-dihydrofuran 5.
Chemoenzymatic synthesis of bis-THF-alcohol 3 by dynamic kinetic resolution of β-ketolactone 8.
Synthesis of (S)-tetrahydrofuran-3-ol 13 from olefinic tosylate 10.
Synthesis of bis-THF-alcohol 3 from benzyloxy butyrolactone 14.
Synthesis of bis-THF-alcohol 3 via Pd-catalyzed asymmetric hydroalkoxylation of ene-alkoxyallene 17 and RCM.
Synthesis of bis-THF-alcohol 3 from 4-benzyloxybutanal 22.
Synthesis of bis-THF-alcohol 3 from spirocyclic dioxolane derivative of D-glyceraldehyde 27.
Synthesis of bis-THF ligands 36 from (S)-glyceraldehyde derivative 30.
Synthesis of bis-THF-alcohol 3 from 1,2-O-isopropylidene-α-D-xylofuranose 38.
Synthesis of bis-THF-alcohol 3 from 3,4-di-O-acetyl-D-arabinal 43.
Synthesis of bis-THF-alcohol 3 from potassium isocitrate 53.
Synthesis of 6–5–5 ring-fused crown-like tetrahydropyranofuran 63 from.
Synthesis of 6–5–5 ring-fused crown-like tetrahydropyranofuran 63 from chiral 3-(acyloxy)acryloyloxazolidinone 65.
Chemoenzymatic synthesis of (1R, 3aS, 5R, 6S, 7aR)-octahydro-1,6-epoxy-isobenzo-furan-5-ol 74.
Synthesis of (1R, 3aS, 5R, 6S, 7aR)-octahydro-1,6-epoxy-isobenzo-furan-5-ol 74 via methyl acetal 76.
Synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol 83 from lactone 80.
Synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol 83 from meso-diacetate 84.
Synthesis of cyclopentanyltetrahydrofurane (Cp-THF) ligands 92 and 93.
Synthesis of oxatricyclic ligands.
Synthesis of gem-difluoro-bis-THF ligands.
Synthesis of cyclohexyl-derived 6-5-5 fused ring ligands and structure of inhibitor 115.
Synthesis of activated isosorbide fragment.
Synthesis of (R)-4,4-dimethyltetrahydrofuran-3-ol 125.
Synthesis of Fornicin A.
Structure of macrocyclic inhibitor 134 and synthesis of key fragment 139.
Synthesis of P2 fragment 139 and final RCM to 134.
Structure of inhibitor DMP 450.
Synthesis of functionalized tetrahydropyrimidinone 150.
Synthesis of unsymmetrical 1,3-diazacycloalkan-2-ones 153.
Synthesis of bis-allylidene-4-piperidone 156.
Synthesis of indolin-2-one inhibitor 161.
Synthesis of 1,4-benzodiazepine dimer inhibitor 166.
Synthesis of 1,4-benzodiazepine-substituted inhibitor 172.
Synthesis of 10b-hydroxy-4-nitro-5-phenyl-2,3,5,5a-tetrahydro-1H-imidazo[1,2-a]indeno[2,1-e]pyridin-6(10bH)-one derivatives 177.
Synthesis of piperidine-substituted inhibitor 181.
Modified macrocyclic peptides.
Synthesis of hydantoin key fragment 189.
Optimized synthesis of 196.
Synthesis of chiral quaternary α-aryl amino acids for iminohydantoins.
Synthesis of thiazolyl fragment of GRL-0355.
6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetics and synthesis of BTG(O)-A.
Synthesis of morpholine key intermediate of MK-8718.
Synthesis of morpholine substituted inhibitor 229.
Synthesis of key indolizine-2-carboxylic acid intermediate.
Synthesis of fluoropyridyl-phenyl-substituted inhibitor 240.
Pentacycloundecane (PCU) diol peptoid 241 and its pyrimidinylthio-substituted derivative 242.
Synthesis of pyridyl substituted inhibitors.
Preparation of activated heteroaromatics.
Synthesis of piperazine-substituted quinolines.
Synthesis of pyrimidine-substituted inhibitor 264.
Synthesis of biaryl-hydrazine unit of Atazanavir.
Synthesis of heteroaryl triterpenes.
Synthesis of N-glucosyl-N′-(4-arylthiazol-2-yl) aminoguanidines.
Synthesis of compound 281.
Retrosynthetic approach to clinical candidate 282.
Diastereoselective synthesis of key epoxide 284.
Synthesis of key intermediate 294.
Approach to isophtalamide inhibitors.
Heteroaryl-modified darunavir scaffolds.
Synthesis of pyridyl-pyrimidine benzamides 303 and pyridyl-thiazolyl inhibitors 308.
Synthesis of key aryl azido triol intermediate.
Synthesis of common heteroaryl PHIQ amino alcohol intermediate.
Synthesis of nelfinavir thienyl analog and saquinavir benzothienyl analog.
Synthesis of non-peptidic heteroaromatic inhibitors.
Synthesis of oxyindoles.
Synthesis of carbamoyl indoles.
Synthesis of heteroaryl amides.
Synthesis of benzyl substituted heteroaryl amides.
Design and synthesis of heteroaryl carbamates.
Synthesis of pseudo-symmetric inhibitors.
Heteroaryl carboxamides with high inhibition activity.
References
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