Synthesis and Biological Evaluation of Chalcone Analogues as HIV Latency Reversing Agents

toxic to host cell and have some side effects [9].Thus, highly efficient and specific drugs for reactivating HIV latency is important for HIV-1 eradication.Chalconoids, natural phenol compounds, have an array of biological activities including anti-inflammatory, antioxidant, antitumor and antibacterial activities and inhibit angiogenesis in vivo and in vitro [10][11][12][13][14]. Chalcone analogues have attracted a great deal of interest due to their synthetic and biological importance in medicinal chemistry.In our previous study, we reported the synthesis and biological evaluation of a chalcone analogue Amt-87, which can significantly reactivate the transcription of latent HIV proviruses and act synergistically with known LRAs such as prostratin and JQ1 to reverse HIV latency [15].Unfortunately, Amt-87 is less active and requires high concentrations to reactivate latent HIV.Herein, we describe the optimization and characterization of the structureactivity relationship (SAR) of chalcone scaffold to generate a series of compounds with enhanced HIV latency reactivation activity. Results Synthesis of Chalcone DerivativesChalcone derivatives 4a-4k were prepared according to a twostep procedure (Scheme 1) previously reported.Condensation of 1-(2-hydroxy-5-methylphenyl)ethanone with 2-or AbstractThe primary barrier of eradicating HIV virus is the existence of latent reservoirs.To overcome this problem, it is urgent to identify specific and effective agents that can activate HIV latent reservoirs and bind with effective anti-retroviral therapy to eventually eliminate HIV virus.In previous study, we reported a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV.However, it is of limited use due to high toxicity.Here, we have synthesized a series of structurally modified analogues of Amt-87 and evaluation for their reactivation of HIV-1 latency revealed one excellent active compound 4k, which can be taken up for further studies.v Scheme 1: Synthesis of chalcone amide derivatives 4a-4k.Reagents and conditions: (a) NaOH, EtOH, r.t., 24 h.(b) various amines, anhydrous HOBt, EDCI, DCM, 12 h.