Background Although major efforts have been devoted to the effective treatment of HIV-1 infection, it has remained one of the leading causes of deaths around the world. So, development of anti-HIV-1 agents featuring novel structure is essential. Objective To synthesize novel quinazolinone derivatives and evaluate their anti-HIV-1 activity. Method In this study, we designed and synthesized a series of novel 2,3-diaryl-4-quinazolinone derivatives using a one-pot multicomponent reaction. Then, the resulting derivatives were evaluated for anti-HIV-1 activity using Hela cell-based single-cycle replication assay. Results Most of the compounds showed efficacy against HIV-1 replication and the compound 9c exhibited the highest activity with EC50 value of 37 μM. Docking studies indicated that synthesized compounds can interact with the key residues of the HIV-1 integrase active site. Binding of the most active compound was consistent with the HIV-1 integrase inhibitors. Conclusion Based on our results, these derivatives represent novel lead compounds for the development of new promising anti-HIV-1 agents.

Design, Synthesis, Docking Studies and Biological Activities Novel 2,3- Diaryl-4-Quinazolinone Derivatives as Anti-HIV-1 Agents

Highly active antiretroviral therapy (HAART) has been widely adopted to control the HIV-1 infection successfully. HIV-1 integrase (IN) inhibitors are primary drugs in HAART regimens targeting integration step in the HIV-1 life cycle. However, due to the emergence of viral resistance and cross-resistance amongst drugs, there is a pressing need for new and potent IN inhibitors. This review covers the three patents describing spirocyclic and phosphate substituted quinolizine derivatives as novel HIV-1 IN inhibitors for the discovery of new anti-HIV-1 drug candidates. Areas covered: This review is focused on spirocyclic and phosphate substituted quinolizine derivatives bearing the same metal chelation scaffold as novel HIV-1 IN inhibitors. Expert opinion: Generally, privileged structure-based optimizations have emerged as an effective approach to discover newly antiviral agents. More generally, due to the similar Mg2+ catalytic active centers of endoribonucleases, some divalent metal ion chelators were found to be versatile binders targeting multiple metalloenzymes. Therefore, privileged structure-based scaffold re-evolution is an important tactic to identify new chemotypes, to explore unknown biological activities, or to provide effective ligands for multiple targets by modifying the existing active compounds.

Identification of spirocyclic or phosphate substituted quinolizine derivatives as novel HIV-1 integrase inhibitors: a patent evaluation of WO2016094197A1, WO2016094198A1 and WO2016154527A1.

Integrase strand transfer inhibitors (INSTIs) are important components of drug formulations that are used to treat people living with HIV, and second-generation INSTIs dolutegravir and bictegravir impart high barriers to the development of drug resistance. Reported 10 years ago, X-ray crystal structures of prototype foamy virus (PFV) intasome complexes explained how INSTIs bind integrase to inhibit strand transfer activity and provided initial glimpses into mechanisms of drug resistance. However, comparatively low sequence identity between PFV and HIV-1 integrases limited the depth of information that could be gleaned from the surrogate model system. Recent high-resolution structures of HIV-1 intasomes as well as intasomes from a closely related strain of simian immunodeficiency virus (SIV), which were determined using single-particle cryogenic electron microscopy, have overcome this limitation. The new structures reveal the binding modes of several advanced INSTI compounds to the HIV/SIV integrase active site and critically inform the structural basis of drug resistance. These findings will help guide the continued development of this important class of antiretroviral therapeutics.

Close-up: HIV/SIV intasome structures shed new light on integrase inhibitor binding and viral escape mechanisms.

Chiral functionalized aminals are important core structures of natural products and pharmaceuticals. Their chemo- and regioselective catalytic, asymmetric synthesis has been realized through the umpolung reaction of α-imino amides using a catalyst we originally developed. Functionalized aminals were prepared with high chemoselectivity by treating a hemiaminal intermediate with pyridine in butanol. Evaluation of substrate scope revealed that this transformation could be achieved with a wide range of α-imino amides to produce the desired products in high yields with up to 97 % ee. A mechanistic study suggested that aminal formation proceeded through the ring opening/ring closing equilibrium of the hemiaminal skeleton.

Chemoselective Catalytic Asymmetric Synthesis of Functionalized Aminals Through the Umpolung Organocascade Reaction of α‐Imino Amides

Synthesis, biological evaluation and in silico modeling of novel integrase strand transfer inhibitors (INSTIs)

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV

[107-71-1] C6H12O3 (MW 132.16)

InChI = 1S/C6H12O3/c1-5(7)8-9-6(2,3)4/h1-4H3

InChIKey = SWAXTRYEYUTSAP-UHFFFAOYSA-N





(radical initiator; often used in the presence of a metal catalyst or photoactivator; free radical initiator for polymer synthesis; common reagent in the metal-mediated acetoxylation of activated CH bonds)



Alternate Names: peroxyacetic acid, tert-butyl ester; acetyl tert-butyl peroxide; tert-butyl peroxyacetate; ethaneperoxoic acid, 1,1-dimethylethyl ester; Esperox 12MD; Kayabutyl A; Kayabutyl A 50T; Luperox 7M75 or 7M50; Lupersol 70; NSC 118417; Perbutyl A; Trigonox F; Trigonox F-C 50.



Physical Data: commercially available as a solution (typically in aliphatic hydrocarbons, 50–75 wt%); colorless to slight yellow liquid; density = 0.83 g mL−1 at 25 °C; flash point = 37 °C.



Solubility: soluble in most organic solvents. Highly soluble in hydrocarbon, ethereal, or chlorinated solvents.



Preparative Methods: acylation of a tert-butyl hydroperoxide with acetyl chloride or acetic anhydride.1 It can also be synthesized from tert-butyl hydroperoxide and acetic acid in the presence of trifluoroacetic anhydride.2



Handling, Storage, and Precautions: as with other organic peroxides, significant care should be taken to minimize rapid, exothermic decomposition that leads to violent and potentially harmful reactions. Decomposition can be triggered by heat, light, and metal contaminants.3 tert-Butyl peracetate has a detected onset temperature of 102 °C and a heat of decomposition of −201 kJ mol−1.4 Recommended storage in a tightly sealed container at 4–23 °C away from heat sources. Contact with skin and eyes or by inhalation should be avoided.

tert‐Butyl Peracetate

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Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV

tert‐Butyl Peracetate