In this study, we have modified 4-hydroxy-pyran-2-ones, especially introduced heteroatoms (S or O) into the substituents, and detected their interactions with the binding pockets of HIV-1 protease (PR). The results indicated that the ethoxyl groups at C-2′ and C-5′ of the phenyl ring could enhance the affinities to the S1′ and S2′ pockets and improve the inhibitory activities. The most potent compound 10f with an IC50 of 3.5 nM in enzymatic assay also exhibited good antiviral activity at the cellular level; it exhibited an EC50 value of 2.9 μM in Simian immunodeficiency virus-infected CEM cells and suppressed the PR activity in 293T cells using western blot analysis.

New anti-HIV-1 drugs that target different viral proteins or genes at various steps in the viral life cycle are highly expected. HIV-1 assembly and disassembly (uncoating) processes are critical for the HIV-1 replication. HIV-1 capsid (CA) and human cyclophilin A (CypA) play essential roles in these processes. Using an in vitro screening system, we evaluated 52 thiourea derivatives for their potential CA and CypA-inhibiting activities. The antiviral activity of these compounds is correlated with their CA assembly inhibitory ability and with their anti-PPIase activity, suggesting that these compounds could block HIV-1 replication by disrupting CA assembly and inhibiting the PPIase activity of CypA to interfere with capsid disassembly. Among them, three compounds D4, D5, and D6 displayed the most promising potency with CA-assembly rate 15.78, 18.42, and 7.97(×10−5) OD/s, and their IC50 for inhibition of PPIase activity 0.45, 0.65, and 0.33 μM, respectively. The potent protein inhibitory activity resulted in their very low EC50 values (≤1.00 μM). They can be used for rational design of novel anti-HIV-1 drugs.

We synthesized a series of acylhydrazone compounds bearing naturally occurring amino acids’ side chains as HIV assembly inhibitors. Biological evaluation indicated that the compounds had anti-SIV and capsid assembly inhibitory activities. The structure–activity relationship (SAR) study showed that compounds bearing proper aromatic side chains had potential antiviral activities. The molecular modeling experiments revealed the molecular mechanism that they could bind to CA in the same manner as CAP-1 and occupy two more grooves.We studied SAR and molecular mechanism of novel acylhydrazone compounds targeting HIV-1 CA. Among synthesized compounds, 8a and 8b possessed the most promising antiviral activities.

HIV-1 assembly and disassembly (uncoating) processes are critical for the HIV-1 replication. HIV-1 capsid (CA) and human cyclophilin A (CypA) play essential roles in these processes. We designed and synthesized a series of thiourea compounds as HIV-1 assembly and disassembly dual inhibitors targeting both HIV-1 CA protein and human CypA. The SIV-induced syncytium antiviral evaluation indicated that all of the inhibitors displayed antiviral activities in SIV-infected CEM cells at the concentration of 0.6–15.8 μM for 50% of maximum effective rate. Their abilities to bind CA and CypA were determined by ultraviolet spectroscopic analysis, fluorescence binding affinity and PPIase inhibition assay. Assembly studies in vitro demonstrated that the compounds could potently disrupt CA assembly with a dose-dependent manner. All of these molecules could bind CypA with binding affinities (Kd values) of 51.0–512.8 μM. Fifteen of the CypA binding compounds showed potent PPIase inhibitory activities (IC50 values < 1 μM) while they could not bind either to HIV-1 Protease or to HIV-1 Integrase in the enzyme assays. These results suggested that 15 compounds could block HIV-1 replication by inhibiting the PPIase activity of CypA to interfere with capsid disassembly and disrupting CA assembly.A series of compounds were prepared to inhibit viral replication by delaying the capsid assembly rate in vitro, and inhibiting PPIase activity of cyclophilin A to disrupt the uncoating process of viral life cycle.

Four compounds were isolated from the root of Dalbergia odorifera T. Chen and identified by chemical and spectroscopic methods as 2′-O-methyl-isoliquiritigenin (1), odoriflavene (2), 5′-methoxy-vestitol (3) and formononetin (4). Their antioxidant activities were investigated in lard by the oxidative stability instrument; their inhibitory effects on the decrease of glutathione level of rat lens induced by UV irradiation were studied using a rat lens UV-damage model, and their in vitro cytotoxicity was measured on human SH-SY5Y neuroblastoma cells. Results indicated that all four compounds had obvious antioxidant effects, while none of them showed any synergistic effects on butylated hydroxytoluene or α-tocopherol. When FeCl3 (4.0 μM) was added, the antioxidant activities of the four compounds markedly decreased. The inhibitory effects of compounds 1, 2 and 4 on the decrease of glutathione level of rat lens induced by UV irradiation were comparable to that of α-tocopherol. All four compounds showed cytotoxic activity when evaluated against a SH-SY5Y cell line in vitro.

Three new complexes [Cu(L)2(NO3)](NO3)(H2O)1/2(CH3OH)1/2 (1), [Cd(L)2(NO3)2](H2O)3 (2) and [Cd(L)2(ClO4)(CH3OH)](ClO4)(H2O)1/4(CH3OH) (3) (L = 1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene) were synthesized and characterized by elemental analyses, IR and X-ray diffraction analysis. Among them, the Cu(II) and Cd(II) ions were both coordinated by four N donors from two distinct L ligands via N,N-bidentate chelating coordination mode. Additional weak interactions, such as the face-to-face π–π stacking and C–H⋯O H-bonding interactions, linked the mononuclear unit into 1D chain and further into 2D network. Complexes 1–3 were subjected to biological assays in vitro against six different cancer cell lines. All of them exhibited cytotoxic specificity and notable cancer cell inhibitory rate. The interactions of 1–3 with calf thymus DNA were investigated by thermal denaturation, viscosity measurements, spectrophotometric and electrophoresis methods. The results indicate that these complexes bound to DNA by intercalation mode via the ligand L and had different nuclease activities, which were in good agreement with their DNA-binding strength. Moreover, the central metal ions of 1–3 played a vital role in DNA-binding behaviors, DNA-cleavage activities and cytotoxicities, whereas the contribution of the different counter anions to their bioactivities also should not be ignored.

A new ligand L, 1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene, and its two metal complexes, [Cu(L)3](ClO4)2 (1) and [Zn(L)3](ClO4)2(H2O)2 (2), have been synthesized and characterized. The crystal structure of complex 1 was determined by single crystal X-ray diffraction, which crystallized in monoclinic, space group P21/n with unit cell parameters, a = 12.710(4) Å, b = 12.135(3) Å, c = 33.450(9) Å, β = 93.281(5)° and Z = 4. The Cu atom was six-coordinated to N(1), N(2), N(4), N(5), N(7) and N(8) from three L ligands and formed a slightly distorted octahedral geometry. Complexes 1 and 2, and ligand L were subjected to biological tests in vitro using three different cancer cell lines (HL-60, BGC-823 and MDA-MB-435). Complex 1 showed significant cytotoxic activity against three cancer cell lines. The interactions of complexes 1 and 2, and ligand L with calf thymus DNA were then investigated by thermal denaturation, viscosity measurements and spectrophotometric methods. The experimental results indicated that complexes 1 and 2 bound to DNA by intercalative mode via the ligand L. The intrinsic binding constants of complexes 1 and 2, and ligand L with DNA were 1.8 × 104, 5.4 × 103 and 2.76 × 103 M−1, respectively.

The study on the interactions between two anti-human immunodeficiency virus type 1 (anti-HIV-1) active compounds with trans-activation response (TAR) RNA by affinity capillary electrophoresis (ACE) with UV absorbance detection is presented. The results showed that the novel active molecules could interact with TAR RNA and inhibit the reproduce process of HIV-1. The binding constants were estimated by the change of migration time of the analytes through the change of concentrations of TAR RNA in the buffer solution. The yielded binding constants of 8.87 × 103 M−1 for active compound C3 and 8.42 × 103 M−1 for MC3 at 20.0 °C, 0.626 × 103 M−1 and 0.644 × 103 M−1 at 37.0 °C, respectively. The thermodynamic parameters ΔH and ΔS were obtained and shown that both hydrophobic and electrostatic interaction played roles in the binding processes. The results showed that the presented method was an easy and simple method to evaluate the interaction of small molecules with some bioactive materials.

A new Mn(II) complex with the planar ligand 6,7-dicycanodipyrido[2,2-d:2′,3′-f]quinoxaline (L) [MnL(NO3)(H2O)3]NO3·CH3OH (1) has been synthesized and characterized by elemental analysis, IR, TG-DTA and molar conductance. Its crystal structure was determined by X-ray diffraction, crystal data: yellow, triclinic, space group P1̄, Z=2, a=7.3743(8) Å, b=11.2487(15) Å, c=14.1655(15) Å, α=79.412(2)°, β=83.208(2)°, γ=80.466(2)°. The Mn atom was hexa-coordinated to form a distorted octahedral geometry by two nitrogen atoms of L and four oxygen atoms of three H2O and NO3− in the complex. The binding mode of the complex with calf thymus DNA has also been investigated with spectrophotometric methods, viscosity and thermal denaturation measurements. The experimental results indicate that the complex intercalated into DNA base pairs via the ligand L. The intrinsic binding constant Kb values for 1 (5.00×105 M−1) and L (1.65×105 M−1) were determined by absorption titration and calculated with the model of McGhee and Von Hippel. Biological tests against four different cell lines (HL-60, KB, Hela and BGC-823) in vitro showed that the complex had significant antitumor properties since the 50% inhibition concentrations (IC50) of the complex were within a μM range similar to those of antitumor drug 5-fluorouracil.