• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Rational drug design, synthesis, and biological evaluation of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamides as potential antimalarial, antifungal, and antibacterial agents

    2021-02-14 07:26:14AhmeHssenShntiShrukKhnGneshTpiyAnnChettuplliShwetSooMohSyeeShikhFlkSiiquiRmkoteswrRoAmr
    Digital Chinese Medicine 2021年4期

    Ahme Hssen Shnti, Shruk Khn, Gnesh Tpiy, Ann Chettuplli, Shwet Soo,Moh Syee Shikh, Flk Siiqui, Rmkoteswr Ro Amr

    a.College of Science for Women, Babylon University, Hilla, Babil 00964, Iraq

    b.MUPs College of Pharmacy (B Pharm), Washim, Maharashtra 444506, India

    c.Shreeyash Institute of Pharmaceutical Education and Research, Aurangabad, Maharashtra 431010, India

    d.Department of Pharmaceutical Sciences, Center for Nanomedicine, Anurag University, Hyderabad 501301, India

    e.Government College of Pharmacy, Karad, Maharashtra 415124, India

    f.Department of Pharmacy, Shri Jagdishprasad Jhabarmal Tibrewala University, Vidya Nagari, Rajasthan 333001, India

    Keywords Sulfonamides Antimalarials Antifungal Antibacterial Plasmodium cysteine protease falcipain-2 2,3-Diphenylquinoxaline-6-sulfonamide Plasmodium falciparum

    ABSTRACT Objective Sulfanilamide, sulfadiazine, and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process, which is essential for parasite survival.Therefore, we aimed to synthesize novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives through a rational drug design approach.Methods All compounds were synthesized by the conventional method, and the products were characterized by spectral analysis(1H NMR and mass spectrometry).The progression of the reaction was monitored using thin-layer chromatography (TLC).All the derivatives were analyzed for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2.Antibacterial and antifungal activities were determined using the broth dilution method.Results S6 (N-(2-thiazol-4yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S9 (N-(1H-benzo[d]imidazol-2-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed five hydrogen bonds; S8 (N-(2-1H-imidazol-2yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S10 (N-(1H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed four hydrogen bonds with the allosteric site of the enzyme.Considering the docking scores and formation of hydrogen bonds with the target enzyme, the novel derivatives were processed for wet lab synthesis.All the newly synthesized derivatives were subjected to in vitro antimalarial, antifungal, and antibacterial activities.All the derivatives exhibited sufficient sensitivity to the Plasmodium falciparum strain compared to the standards.Moreover, compounds S9 and S10 showed the most potent dual antimicrobial and antimalarial activities.They also exhibited powerful molecular interactions in molecular docking studies.Conclusion Based on the above results, it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial, antifungal, and antibacterial agents.

    1 Introduction

    Malaria poses a critical public health threat and a significant financial burden in malaria-endemic countries[1].There has been increased attention and new affirmation to the suppression of malaria, which has steadily resulted in over a million deaths, and drug safety from each new chemotherapeutic methodology, particularly inPlasmodium falciparum, the parasite responsible for nearly all malaria-related deaths[2].According to the World Malaria Report 2020 statistics, in 2019, there were an estimated 229 million cases of malaria worldwide.The estimated number of malaria deaths was 409 000 in 2019.Children under 5 years of age are the most vulnerable group affected by malaria; they accounted for 67%(274 000) of all malaria deaths worldwide in 2019[3].Plasmodium ovale, Plasmodium vivax, Plasmodium falciparum, andPlasmodium malariaeare the four varieties of human malaria spread by mosquitos[4].The first two are the most common, whereasPlasmodium falciparum, often present in Africa, accumulates in organ failures and brain capillaries, eventually leading to coma and death.There is evidence that the mortality attributable toPlasmodium vivaxis underestimated[5].Falcipain-2, the predominant cysteine protease ofPlasmodium falciparum, the mammalian malaria parasite, is a hemoglobinase and a potential therapeutic target[6].

    Modernization and behavioral changes negatively affect people's lives, including their physical and mental well-being.This abnormal human state and numerous toxins attract many pathogens, including infectious, fungal, and plasmodial[7,8].The scientific community has been working to inhibit or eliminate these diseases worldwide.Drug molecules derived from biological sources and synthetic analogs have been used to treat infectious disorders.Most of these natural products are heterocyclic, according to structural analysis[2,4,5].

    Millions of humans are now affected by bacterial diseases triggered by pathogenic bacteria, responsible for elevated child mortality rates in developed countries[9].Not all bacteria are pathogenic.For example, there are thousands of bacterial organisms in the human digestive tract, some of which are harmless and even useful.Furthermore, various mechanisms of action on the target site can aid in discovering potential drugs for the development of antibacterial agents[10].However, since bacteria have developed antibiotic tolerance, it has become difficult to find new antibacterial agents.Gram-positive bacteria, such as methicillin-resistantStaphylococcus aureus, Staphylococcus epidermis,vancomycin-resistantEnterococci,and penicillin-resistantStreptococcus pneumoniae, induce most bacterial infections.Fungal infections have become more frequent, with the majority being of low severity[11].Various varieties of fungi cause infections[12], such asCandidaandAspergillus[13].

    Sulfonamides are antimalarial drugs that disrupt the folate biosynthesis process, which is essential for parasite survival.The first sulfa medications used to prevent malaria infections were sulfanilamide, sulfadiazine, and dapsone[5].It has been well documented that heterocyclic compounds isolated from natural sources possess diverse antimicrobial[14], antifungal[15], and antimalarial[16]biological activities.Alkaloids are heterocyclic nitrogen-containing chemicals that exhibit a wide range of antibacterial activities.Quinine is a cinchona alkaloid that belongs to the aryl amino alcohol class of medicines.It has a rapid schizonticidal effect against intra-erythrocytic malarial parasites[17].Therefore, to obtain more potent heterocyclic compounds, we investigated the nitrogen, sulfur, and oxygen atoms containing heterocyclic scaffolds.We have designed and synthesized novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives.All the derivatives have been studied for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2.Considering the docking scores and formation of hydrogen bonds with the target enzyme,the novel derivatives were processed for wet lab synthesis.All the newly synthesized products were subjected toin vitroantimalarial, antifungal, and antibacterial evaluations.

    2 Materials and methods

    2.1 Design of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamides

    2,3-Diphenyl quinoxaline and sulfonamides are an imperative class of nitrogen and sulfur-inclosing heterocycles with diverse pharmacological profiles[18–26].In this study, we designed and synthesized novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives.The designed derivatives were screened by molecular docking.A total of 10 derivatives were designed, as shown in Figure 1.Derivatives with excellent binding affinities, followed by the formation of potent hydrogen bonds with an allosteric site of the target enzyme, were selected for the synthesis.

    2.2 Molecular docking (MD) simulation

    We used Autodock Vina 1.1.2 in PyRx-Virtual Screening Tool 0.8 to execute the MD on a Lenovo Think-Pad T440p[27].The structures of all the derivatives were sketched in ChemDraw Ultra 8.0 and saved in molfile format.Energy minimization (optimization)was executed using a universal force field (UFF)[28].

    The crystal structure ofPlasmodium falciparumcysteine protease falcipain-2(PDB ID:1YVB,https://www.rcsb.org/structure/1YVB) was obtained from the RCSB Protein Data Bank (PDB).No inhibitor/native ligand was present in the 1YVB.With the aid of Discovery Studio Visualizer 2019, the enzyme structure was optimized, purified, and prepared for MD[29].The crystal structures ofPlasmodium falciparumcysteine protease falcipain-2 crystal structure are illustrated in Table 1.

    The derivatives and target enzyme file structures were then imported into PyRx software and converted to pdbqt format.The molecules (pdbqt files), both ligands, and targets were selected for MD[30].For the MD simulation, a three-dimensional (3D) grid box(size x =39.101 492 977 7 ?; size y= 43.678 539 274 3 ?;size z = 39.698 857 395 7 ?) was built using Autodock tool 1.5.6, with an exhaustiveness value of 8[31].The active amino acids in the protein were examined using a BIOVIA Discovery Studio Visualizer (version-19.1.0.18287)[27].In the complete MD method, the cavity and active amino acid residues were identified per the procedure described by KHAN et al.[30–35].The purified structure of the enzyme is shown in Figure 2.

    Figure 1 Designing of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives

    Table 1 The essentials of the crystal structure of the Plasmodium falciparum cysteine protease falcipain-2

    Figure 2 A purified structure of the Plasmodium falciparum cysteine protease falcipain-2

    2.3 Screening through Lipinski rule of five

    The designed derivatives were checked to exceed Lipinski's rule of five, and the ones that passed were further tested for compliance.The properties of the derivatives were measured using the SwissADME online tool (http://www.swissadme.ch/index.php).

    2.4 Wet lab synthesis

    Synthetic grade chemicals and reagents were purchased from Lab Trading Laboratory, Aurangabad,Maharashtra, India.The melting points were measured using a VEEGO MODEL VMP-D melting point apparatus.Thin-layer chromatography (TLC) was used to validate the completion of reactions using preparative TLC plates (Merck precoated silica GF 254).Qualitative tests were used to validate functional group conversions.On a Varian-VXR-300S at 300 MHz NMR spectrometer,1H and13C NMR spectra were reported with DMSO as the solvent and TMS as the internal standard; chemical shift values were expressed inδppm.The solutions were kept in high performance liquid chromatography(HPLC)grade methanol for mass spectra, and spectra were generated using electron ionization at 70 eV.

    2.4.1 Synthesis of parent nucleusIn the first step,chlorosulfonation of 2,3-diphenyl quinoxaline was performed to yield 2,3-diphenylquinoxaline-6-sulfonyl chloride.In an ice-cold fuming cupboard with continuous stirring, 2,3-diphenylquinoxaline (0.01 mol,2.84 gm) was treated with chlorosulfonic acid.The reaction mixture was stirred until the temperature reached room temperature (25 ? 30 °C).The resulting mixture was dissolved in water to produce 2,3-diphenylquinoxaline-6-sulphonyl chloride.In the second step,N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide was synthesized from the product obtained in the first step.O-phenylenediamine (0.01 mmol, Batch No.MCR-19023-01) was dissolved in dichloromethane (20 mL) in a beaker.In another beaker, pyridine (1.6 mL, Batch No.MCRT-20839) was progressively added to a solution of 2,3-diphenylquinoxaline-6-sulfonyl chloride (1.93 gm,10 mmol) in dichloromethane (10 mL, Batch No.MCR-4126) at 0 °C.Both solutions were combined,and the reaction mixture was agitated at room temperature for 1.5 h before being washed with aqueous 1 mol/L HCl (Batch No.MCR-24517) and brine and dried over Na2SO4(Batch No.MCR-24118).The crude product was recrystallized in dichloromethane after evaporating the organic solvent, and N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide was collected as a light-yellow solid[36,37].

    2.4.2 Synthesis of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivativesIn a 250 mL RBF, an appropriate chloro-substituted heterocyclic compound (0.01 mol) and K2CO3(0.02 mol,2.76 gm, Batch No.MCR-24331) were agitated at room temperature in dimethylformamide (DMF, 20 mL,Batch No.MCR-22588) for 30 min; KI (Batch No.MCR-24 288) pinch was added to the solution.N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide (0.01 mol) was added to the reaction mixture.The reaction was refluxed for 12 h until TLC showed reaction accomplishment.The reaction mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (3 times and 20 mL for each) using a separating funnel.The organic extracts were washed with water, dried over anhydrous sodium sulfate, and condensed to produce a crude product.To obtain a pure compound, the residue was recrystallized from diethyl ether[38].The chemical reactions are shown in Figure 3.

    2.5 In vitro biological evaluation

    Figure 3 The proposed reaction scheme for the synthesis of novel derivatives

    Various concentrations of the derivatives were prepared in DMSO (Batch No.MCR-18421-01) to assess their antibacterial and antifungal activities against standard strains using broth dilution.Bacteria were maintained, and the drugs were diluted in Mueller-Hinton broth.The broth was inoculated with 108colony-forming units (cfu) per milliliter of test strains(Institute of Microbial Technology, Chandigarh, India) determined by turbidity.Stock solutions of the synthesized derivatives (2 mg/mL) were serially diluted for primary and secondary screening.The primary screen included 1 000, 500, and 250 μg/mL of synthesized derivatives, and those with activity were further screened at 200, 100, 50, 25, 12.5, and 6.250 μg/mL.A control without antibiotic was subcultured (before inoculation) by spreading one loopful evenly over a quarter of a plate of medium suitable for growing test organisms and incubated at 37°C overnight.The lowest concentrations of derivatives that inhibited bacterial or fungal growth were considered minimal inhibitory concentrations(MICs).These were compared with the amount of control growth before incubation (original inoculum)to determine the MIC accuracy.The standards for antibacterial activity were gentamycin,ampicillin,chloramphenicol,ciprofloxacin,and norfloxacin served, and those for antifungal activity were nystatin and griseofulvin[33].The antimalarial behavior was tested usingPlasmodium falciparum, with quinine and chloroquine as standards[39].Both experiments were conducted at the Microcare Laboratory and Tuberculosis Research Centre (TRC) in Surat, Gujarat.

    3 Results

    3.1 MD Simulation

    The molecular formula, ligand energy (kcal/mol),binding affinities of conformers (kcal/mol) withPlasmodium falciparumcysteine protease falcipain-2,and root mean square deviation (rmsd)/upper bound(ub) and lower bound (lb) of the designed derivatives are tabulated in Table 2.The active amino acid residues, active atoms from ligands, bond length (?),bond type, and bond category of molecules with falcipain-2 are shown in Table 3.The 3D- and 2D-docking poses of the molecules in the allosteric site of falcipain-2 are shown in Table 4.Calculated druglikeness properties (rule of five) of the molecules are shown in Table 5.

    3.2 Characterization data of the synthesized molecules

    From virtual screening, it was concluded that molecules S6, S8, S9, and S10 exhibited high binding affinity for the formation of more than two hydrogen bonds with falcipain-2.Considering this, we proceeded with synthesizing these four molecules, followed by their characterization and biological activity.1H NMR and mass spectroscopy confirmed the synthesis of the compounds.The spectra are provided in the supplementary file.

    N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide(Parent Nucleus)

    King Cloverleaf and Queen Frivola had but one child, and this Princess had from her very babyhood been so beautiful, that by the time she was four years old the Queen was desperately2 jealous of her, and so fearful that when she was grown up she would be more admired than herself, that she resolved to keep her hidden away out of sight

    Yield: 48%; color: pale yellow solid; solubility: ethanol, acetone, benzene; melting point: 100 – 101 °C;Rfvalue: 0.68; elemental analysis (calc.): C, 69.01; H,4.45; N, 12.38; O, 7.07; S, 7.09.1H NMR (DMSO-d6300 MHz)δppm: 4.0 (s, -NH2, -NH), 6.23, 6.39 (s, 4H,Ar-H), 7.39 ? 7.69 (d, diphenyl Ar-H), 8.16, 8.44 (d,2H, Ar-H).MS: m/z 451.76, 455.01 (m +1), 456.20(m +2).

    S6(N-(2-thiazol-4yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide

    Yield: 63%; color: light orange; solubility: ethanol,benzene, slightly soluble in hot water; melting point:111 ? 113 °C; Rfvalue: 0.78; elemental analysis (calc.):C, 64.45; H, 4.01; N, 12.12; O, 8.31; S, 11.10.1H NMR(DMSO-d6300 MHz)δppm: 2.4 (s, -CH3), 4.0 (s, -NH,-NH), 6.24, 6.36 (s, 4H, Ar-H), 7.32 ? 7.91 (d, diphenyl Ar-H), 8.45, 8.43, 8.62 (d, 2H, Ar-H).MS: m/z 576.36,578.23 (m+1), 579.45 (m+2).

    S8(N-(2-1H-imidazol-2yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide

    Yield: 81%; color: light orange; solubility: ethanol,benzene, water; melting point: 120 ? 122 °C; Rfvalue:0.63; elemental analysis (calc.): C, 67.17; H, 4.28; N,16.21; O, 6.17; S, 6.18.1H NMR (DMSO-d6300 MHz)δppm: 4.0 (s, -NH, -NH), 6.23, 6.37 (s, 4H, Ar-H), 7.23(d, 2H, Imidazole), 7.34 ? 7.49 (d, diphenyl Ar-H),8.15, 8.16, 8.42, 8.7 (d, 2H, Ar-H).MS: m/z 513.32,518.20 (m +1), 520.45 (m +2).

    Table 2 The -Ar group, molecular formula, ligand energy (kcal/mol), binding affinities of conformers (kcal/mol)rmsd/ub, and rmsd/lb of designed derivatives

    Table 2 Continued

    Table 3 The active amino acid residues, active atom from ligands, bond length (?), bond type and bond category of molecules with falcipain-2

    Table 3 Continued

    Table 4 3D- and 2D-docking poses of the molecules in allosteric site of falcipain-2

    Table 5 Calculated druglikeness properties (rule of five) of the molecules

    Yield: 52%; color: light yellow; solubility: ethanol,benzene; melting point: 123 ? 125 °C; Rf value: 0.73;elemental analysis (calc.): C, 69.70; H, 4.25; N, 14.78;O, 5.63; S, 5.64.1H NMR (DMSO-d6300 MHz)δppm:4.4 (s, -NH, -NH), 5.0 (s, -NH imidazole), 6.23, 6.38 (s,4H, Ar-H), 7.48 ? 7.59 (d, diphenyl Ar-H), 8.01, 8.37(d, 2H, Ar-H).MS: m/z 564.30, 567.83 (m+1), 569.34(m+2).

    S10(N-(1H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide

    Yield: 67%, color: light yellow; solubility: ethanol,benzene; melting point: 118 ? 120 °C; Rf value: 0.60;elemental analysis: C =69.70; H =4.25; N =14.78; O =5.63; S =5.64.1H NMR (DMSO-d6300 MHz)δppm:4.2 (s, -NH, -NH), 4.9 (s, -NH imidazole), 6.23, 6.38 (s,4H, Ar-H), 7.1 (d, 1H, Ar-H of benzimidazole), 7.51 ?7.89 (d, diphenyl Ar-H), 8.11 (d, 1H, imidazole), 8.29 ?8.37 (d, 2H, Ar-H).MS: m/z 571.34, 574.75 (m+1),575.45 (m+2).

    3.3 In vitro biological activity

    The results of antimicrobial, antifungal, and antimalarial activities of the synthesized derivatives are tabulated in Table 6 shows the MICs, minimum fungicidalconcentrations (MFCs), and Half-maximal inhibitory concentration (IC50) values, respectively.

    Table 6 Antimicrobial, antifungal, and antimalarial activities of the synthesized derivatives

    4 Discussion

    For many years, quinine has been the most effective antimalarial medicine; however, since the 1930s, synthetic drugs such as 8-aminoquinolines (e.g., primaquine), 4-aminoquinolines (e.g., chloroquine, amodiaquine), sulfonamides (e.g., sulfadoxine), and sulfones and folic acid biosynthesis inhibitors have essentially supplanted it (e.g., proguanil and pyrimethamine).Malaria was widely anticipated to be eliminated globally by the mid-1950s; however, in the mid-1960s, this confidence had been shattered due to resistance issues[40].As an alternative to chloroquine,some researchers have focused their efforts on the discovery of novel active molecules, particularly artemisinin.At present, no single medicine is helpful for treating multidrug-resistant malaria; therefore,successful combination treatment includes artemis inin derivatives such as artesunate or combinations of earlier drugs such as atovaquone and proguanil.There have been cases of drug resistance to artemisinin derivatives and pharmacological combination therapy.As a result, attempts to develop novel antimalarial medications are urgently required because of the lack of a viable, safe, and widely accessible malaria vaccine[41].Therefore, novel 2,3-diphenylquinoxaline-6-sulfonamides derivatives were designed by considering their potential biological activities.A parent nucleus was synthesized as N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide, from which 10 novel derivatives were designed using different chloro-substituted hetero/homocyclic compounds.These 10 derivatives were studied for their binding affinity towards the allosteric site of the cysteine protease falcipain-2 ofPlasmodium falciparum(PDB ID: 1YVB).It was observed that compounds S6, S8, S9, and S10 possess excellent binding affinity and formed sufficient hydrogen bonds with the amino acids of the target enzyme.Therefore, we decided to synthesize these four derivatives, followed by their characterization andin vitrobiological evaluation.

    Nine conformers of each molecule were generated through MD.A confirmer with zero rmsd/ub and rmsd/lb was considered the best binding model for the molecule.Compound S1 exhibited – 8.4 a binding affinity and formed one conventional hydrogen bond with TRP177 (2.835 13 ?).Many hydrophobic interactions have been developed through the Pi-orbital system with ALA142 [Pi-sigma(bond type):3.709 45 ?, Pi-alkyl: 4.946 93 ?], TRP177 (Pi-Pi stacked; 4.253 42 ?, 3.954 37 ?, 3.726 89 ?, 4.321 78 ?),and TRP181 (Pi-Pi T-shaped; 5.109 05 ?).Compound S2 demonstrated – 8.6 kcal/mol binding affinity and formed one conventional hydrogen bond with TRP177 (2.996 14 ?) and exhibited hydrophobic interactions with ALA142(Pi-sigma; 3.765 71 ?),TRP177 (Pi-Pi stacked; 4.218 6 ?, 3.964 96 ?, 3.737 37 ?,4.367 26 ?), and TRP181 (Pi-Pi T-shaped; 5.114 8 ?).Compound S3 formed two conventional hydrogen bonds with TRP177 (2.221 4 ?, 2.615 19 ?) through the hydrogen atoms of both -NH and exhibited – 9.1 a binding affinity.It developed hydrophobic interactions in the same way as compound S2.Compound S4 displayed – 9 kcal/mol binding affinity and formed two conventional hydrogen bonds with TRP177(2.574 03 ?, 2.340 77 ?) through the hydrogen atoms of both -NH groups.One electrostatic bond was formed with ASP18 (Pi-anion; 3.472 25 ?) and established hydrophobic interactions with ALA142 (Pisigma; 3.579 62 ?) and TRP177 (Pi-Pi stacked;4.146 35 ?, 3.852 12 ?, 3.642 99 ?, 4.231 43 ?).Compound S5 showed a – 8.8 kcal/mol docking score and exhibited the same binding interaction as shown by compound S5.Compound S6 exhibited – 9.4 kcal/mol binding affinity, and formed five conventional hydrogen bonds with LYS20 (2.090 03 ?) through the hydrogen of -NH, GLN19 (2.680 3 ?) through sulfonyl oxygen, CYS25 (2.534 08 ?) through sulfonyl oxygen,and HIS159 (2.735 23 ?, 2.271 42 ?) through a sulfonyl oxygen atom.A Pi-sulfur bond was formed with CYS25 (4.885 39 ?) through the Pi-orbitals of the aromatic ring system.It developed very potent hydrophobic interactions with TRP177 (Pi-Pi stacked;4.065 1 ?, 4.386 7 ?), LYS20:C, O; ASN21:N (Amide-Pi stacked, 3.822 58 ?), ALA142 (Pi-alkyl; 5.346 04 ?),and LYS20 (Pi-alkyl; 5.185 73 ?).Compound S7 exhibited ? 8.8 kcal/mol binding affinity and formed two hydrogen bonds with TRP177 (2.395 94 ?,2.518 76 ?) through hydrogen atoms of both -NH groups.It developed electrostatic interactions and many hydrophobic interactions with the target.Compound S8 formed two conventional hydrogen bonds with TRP177 (2.666 44 ?, 2.987 66 ?) through the hydrogen of free -NH and -NH of the imidazole ring and one carbon-hydrogen bond with ASP18 (3.398 79 ?)with – 8.9 a binding affinity.It exhibited hydrophobic interactions similar to those exhibited by S2.Compound S9 exhibited a binding free energy of– 10 kcal/mol, formed five conventional hydrogen bonds, and developed many hydrophobic interactions with the same amino acids formed by compound S6.Compound S10 showed – 9.9 kcal/mol binding affinity and formed four conventional hydrogen bonds with ASN158 (1.933 16 ?, 2.111 79 ?)through hydrogen atoms of both -NH, ASP205(2.034 98 ?) through hydrogen atom of -NH of benzimidazole, CYS25 (2.969 29 ?) through a sulfonyl oxygen atom.It has developed hydrophobic interactions with TRP177 (Pi-Pi stacked; 3.715 63 ?, 3.978 15 ?),LEU67 (Pi-alkyl; 5.444 47 ?), and ALA142 (Pi-alkyl;4.145 ?, 5.465 44 ?).Based on the above results, it was decided to perform the wet lab synthesis of compounds S6, S8, S9, and S10.The druglikeness properties (rule 5) were calculated for all the designed derivatives.The derivatives showed one violation due to a molecular weight higher than 500 Da.It was observed that LYS20, GLN19, CYS25, HIS159, TRP177,ASN158, and ASP205 play a crucial role in binding with the ligands by forming conventional hydrogen bonds.

    The antimicrobial activity of the synthesized compounds was tested against gram-positive (Staphylococcus aureusandStaphylococcus pyogenes) and gram-negative (Escherichia coliandPseudomonas aeruginosa) bacteria.All the compounds demonstrated more potent activity than ampicillin against gram-positive and gram-negative bacteria.Compounds S6, S9, and S10, were sensitive at 25 μg/mL,which was equipotent to ciprofloxacin againstPseudomonas aeruginosa.Compound S6 was sensitive toStaphylococcus aureusat 25 μg/mL, S8 at 50 μg/mL, S9 at 25 μg/mL, and S10 at 25 μg/mL.All the compounds exhibited more potency than ampicillin, chloramphenicol, and ciprofloxacin.All compounds were sensitive toStaphylococcus pyogenes.Antifungal activity was performed onCandida albicans,Aspergillus niger, andAspergillus clavatusstrains using nystatin and Greseofulvin as standards.Compounds S9 and S10 demonstrated equipotent activity(100 μg/mL) as standards against all fungal strains.All the compounds showed more potent activity againstC.albicansthan Greseofulvin.

    Antimalarial activity was assessed usingPlasmodium falciparum.As the derivatives were screened by MD studies on cysteine protease falcipain-2 ofPlasmodium falciparum(PDB ID: 1YVB),the results ofin vitrobiological evaluation support the results obtained from MD.Quinine and chloroquine were used as the standards.All the synthesized compounds were sensitive toPlasmodium falciparum.Compound S6 showed IC50value of 0.58 μg/mL, compound S8 0.76 μg/mL, compound S9 0.42 μg/mL, and compound S10 showed 0.46 μg/mL againstPlasmodium falciparum.Many synthetic compounds have been reported as cysteine protease falcipain-2 inhibitors[42–45]for the treatment of malaria; however, the present investigation provided a novel lead nucleus for further optimization to generate more potent derivatives.

    5 Conclusion

    Sulfonamides are antimalarial drugs that disrupt the folate biosynthesis process, which is essential for parasite survival.The first sulfa medications to prevent malaria infections were sulfanilamide, sulfadiazine, and dapsone.We have designed and synthesized novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives.Considering the docking scores and formation of hydrogen bonds with the target enzyme, novel derivatives were used for wet lab synthesis.All the newly synthesized products were subjected toin vitroantimalarial, antifungal, and antibacterial evaluations.A parent nucleus was synthesized as N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide, from which 10 novel derivatives were designed using different chloro-substituted hetero/homocyclic compounds.Based on the above results, it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial, antifungal, and antibacterial agents.It can be treated as a lead nucleus to further novel therapeutically active compounds.

    Competing interests

    The authors declare no conflict of interest.

    多毛熟女@视频| 免费av毛片视频| 99久久久亚洲精品蜜臀av| 国产又爽黄色视频| 一夜夜www| 桃红色精品国产亚洲av| 亚洲七黄色美女视频| 亚洲精品国产精品久久久不卡| 国产一区二区三区综合在线观看| 嫩草影院精品99| 午夜精品在线福利| 久久热在线av| 不卡一级毛片| 在线免费观看的www视频| 性色av乱码一区二区三区2| 精品无人区乱码1区二区| 欧美最黄视频在线播放免费 | 色哟哟哟哟哟哟| 国产av一区二区精品久久| 一夜夜www| 在线av久久热| 亚洲va日本ⅴa欧美va伊人久久| 亚洲少妇的诱惑av| 日韩欧美三级三区| 精品国产一区二区三区四区第35| 欧美中文日本在线观看视频| 中文字幕人妻丝袜一区二区| 乱人伦中国视频| a级毛片在线看网站| 高清黄色对白视频在线免费看| 久久人妻福利社区极品人妻图片| 亚洲欧美一区二区三区黑人| a级毛片在线看网站| 久9热在线精品视频| 国产精品美女特级片免费视频播放器 | 国产亚洲精品久久久久5区| 免费人成视频x8x8入口观看| 最近最新免费中文字幕在线| 一夜夜www| 亚洲精华国产精华精| 天堂√8在线中文| 丁香欧美五月| 久热这里只有精品99| 91精品三级在线观看| 国产精品av久久久久免费| 亚洲av熟女| 亚洲一区二区三区欧美精品| 91麻豆av在线| 欧美精品亚洲一区二区| 久久精品国产亚洲av香蕉五月| 高清黄色对白视频在线免费看| 成年女人毛片免费观看观看9| 国产熟女xx| 日本免费一区二区三区高清不卡 | 久久精品91无色码中文字幕| 免费av中文字幕在线| 亚洲午夜精品一区,二区,三区| 啦啦啦免费观看视频1| 18禁美女被吸乳视频| 亚洲一区高清亚洲精品| 国产精品国产高清国产av| 在线观看一区二区三区激情| 久久久久久久久久久久大奶| 色尼玛亚洲综合影院| 欧美日韩av久久| 国产xxxxx性猛交| 精品免费久久久久久久清纯| √禁漫天堂资源中文www| 精品福利观看| 日韩欧美三级三区| 无人区码免费观看不卡| 一本大道久久a久久精品| 国产av在哪里看| 午夜福利在线免费观看网站| 婷婷丁香在线五月| 欧美成人午夜精品| 日韩欧美三级三区| 久久久精品国产亚洲av高清涩受| 国产免费男女视频| 成人三级黄色视频| 久久精品91无色码中文字幕| 国产99久久九九免费精品| 免费在线观看影片大全网站| av在线天堂中文字幕 | 久久婷婷成人综合色麻豆| 日本黄色日本黄色录像| av片东京热男人的天堂| 亚洲欧美精品综合一区二区三区| 他把我摸到了高潮在线观看| 久久久精品欧美日韩精品| 午夜福利在线观看吧| 久久精品成人免费网站| 国产成人精品久久二区二区91| 色婷婷av一区二区三区视频| 手机成人av网站| 日韩欧美一区视频在线观看| 久久九九热精品免费| 国产精品一区二区免费欧美| 欧美+亚洲+日韩+国产| 久久久精品欧美日韩精品| 亚洲一区高清亚洲精品| 国产精品99久久99久久久不卡| 另类亚洲欧美激情| 真人一进一出gif抽搐免费| 日韩大尺度精品在线看网址 | 日本黄色日本黄色录像| 国产单亲对白刺激| 色婷婷久久久亚洲欧美| 亚洲,欧美精品.| 欧美成狂野欧美在线观看| 窝窝影院91人妻| 男人舔女人的私密视频| 狠狠狠狠99中文字幕| 亚洲国产中文字幕在线视频| 老汉色∧v一级毛片| 欧美激情极品国产一区二区三区| 91麻豆av在线| 麻豆久久精品国产亚洲av | 日韩精品中文字幕看吧| 亚洲成av片中文字幕在线观看| 99香蕉大伊视频| 亚洲av成人一区二区三| 丰满的人妻完整版| 欧美成狂野欧美在线观看| 亚洲精品av麻豆狂野| 亚洲精品在线观看二区| 日本免费a在线| 亚洲avbb在线观看| 久久久久久免费高清国产稀缺| 国产三级黄色录像| 欧美日韩亚洲国产一区二区在线观看| 精品一区二区三区视频在线观看免费 | 国产黄色免费在线视频| 一区二区三区国产精品乱码| 久久精品aⅴ一区二区三区四区| 一边摸一边抽搐一进一小说| 国产精品一区二区免费欧美| 亚洲国产毛片av蜜桃av| 大香蕉久久成人网| 国产成人精品久久二区二区免费| 欧美黑人精品巨大| 久久午夜亚洲精品久久| 又黄又粗又硬又大视频| 99国产精品免费福利视频| 久9热在线精品视频| 在线观看舔阴道视频| 天天影视国产精品| √禁漫天堂资源中文www| 曰老女人黄片| 99精品欧美一区二区三区四区| 91国产中文字幕| 日日爽夜夜爽网站| 无遮挡黄片免费观看| 免费搜索国产男女视频| 一级毛片高清免费大全| 久久精品国产亚洲av香蕉五月| 制服诱惑二区| 精品久久久精品久久久| 深夜精品福利| 免费在线观看黄色视频的| 美国免费a级毛片| avwww免费| 18禁裸乳无遮挡免费网站照片 | 成人手机av| 成人精品一区二区免费| 国产精品久久久人人做人人爽| 嫁个100分男人电影在线观看| 久久 成人 亚洲| 亚洲欧美日韩无卡精品| 一级,二级,三级黄色视频| 一级毛片女人18水好多| 国产主播在线观看一区二区| 老司机午夜十八禁免费视频| 精品国产亚洲在线| 亚洲七黄色美女视频| 最近最新中文字幕大全电影3 | 精品久久久久久电影网| 亚洲男人的天堂狠狠| 亚洲色图综合在线观看| 亚洲欧美精品综合一区二区三区| 欧美在线黄色| 中文字幕另类日韩欧美亚洲嫩草| 男人的好看免费观看在线视频 | 国产1区2区3区精品| 亚洲中文字幕日韩| 精品国产一区二区三区四区第35| 国产精品av久久久久免费| 午夜老司机福利片| 免费在线观看日本一区| 成人特级黄色片久久久久久久| 亚洲av成人av| 午夜久久久在线观看| 欧美亚洲日本最大视频资源| 18禁美女被吸乳视频| 亚洲情色 制服丝袜| 神马国产精品三级电影在线观看 | 一级a爱视频在线免费观看| 88av欧美| 精品久久蜜臀av无| 丰满饥渴人妻一区二区三| 露出奶头的视频| 91麻豆av在线| 久久久久亚洲av毛片大全| 国产精品 国内视频| 欧美最黄视频在线播放免费 | 久久久精品国产亚洲av高清涩受| av免费在线观看网站| 久久精品国产清高在天天线| 中文字幕色久视频| 精品电影一区二区在线| 久久亚洲真实| 国产亚洲精品一区二区www| 1024香蕉在线观看| 亚洲欧美精品综合久久99| 欧美亚洲日本最大视频资源| 久久精品91无色码中文字幕| 中文字幕精品免费在线观看视频| 在线免费观看的www视频| 国产97色在线日韩免费| 老熟妇仑乱视频hdxx| 亚洲一码二码三码区别大吗| 一级毛片精品| av视频免费观看在线观看| 99久久国产精品久久久| 妹子高潮喷水视频| 一个人观看的视频www高清免费观看 | 中文字幕色久视频| 亚洲国产欧美日韩在线播放| 亚洲一区二区三区欧美精品| 欧美日韩瑟瑟在线播放| 露出奶头的视频| 搡老乐熟女国产| 乱人伦中国视频| 十八禁人妻一区二区| 9191精品国产免费久久| 国产黄a三级三级三级人| 国产精品久久电影中文字幕| 天天躁狠狠躁夜夜躁狠狠躁| 久99久视频精品免费| 一边摸一边抽搐一进一出视频| 国产一区二区三区综合在线观看| 制服人妻中文乱码| 久久国产精品男人的天堂亚洲| 99在线视频只有这里精品首页| 手机成人av网站| 久久久国产精品麻豆| 黑人猛操日本美女一级片| 97碰自拍视频| 最近最新免费中文字幕在线| 高清在线国产一区| 久热爱精品视频在线9| 老熟妇仑乱视频hdxx| 亚洲av美国av| 欧美成人性av电影在线观看| 亚洲成国产人片在线观看| 在线观看www视频免费| 免费女性裸体啪啪无遮挡网站| 50天的宝宝边吃奶边哭怎么回事| 国产精品香港三级国产av潘金莲| e午夜精品久久久久久久| 精品国产超薄肉色丝袜足j| 久久精品国产亚洲av高清一级| 国产1区2区3区精品| 欧美午夜高清在线| 成人三级做爰电影| 久久久国产欧美日韩av| 久久这里只有精品19| 黄网站色视频无遮挡免费观看| 少妇裸体淫交视频免费看高清 | 精品一区二区三卡| 夜夜夜夜夜久久久久| 欧美日韩黄片免| 久久久久久久精品吃奶| 成人精品一区二区免费| 啦啦啦 在线观看视频| 国产av一区在线观看免费| 亚洲少妇的诱惑av| 成人黄色视频免费在线看| 777久久人妻少妇嫩草av网站| 天天添夜夜摸| 一级毛片精品| 天堂√8在线中文| www.熟女人妻精品国产| 日韩 欧美 亚洲 中文字幕| 精品一区二区三区四区五区乱码| 一进一出抽搐gif免费好疼 | 国产免费男女视频| videosex国产| 黄色a级毛片大全视频| 精品一区二区三卡| aaaaa片日本免费| 在线观看免费视频日本深夜| 交换朋友夫妻互换小说| 欧美人与性动交α欧美软件| 丝袜美腿诱惑在线| 国产成人精品久久二区二区免费| 国产亚洲欧美在线一区二区| 黄色怎么调成土黄色| 波多野结衣av一区二区av| 国产熟女午夜一区二区三区| 动漫黄色视频在线观看| 亚洲一区二区三区欧美精品| 久久精品亚洲熟妇少妇任你| 欧美日韩乱码在线| 香蕉久久夜色| 国产一区二区三区在线臀色熟女 | 免费女性裸体啪啪无遮挡网站| 在线观看免费高清a一片| 亚洲男人天堂网一区| 日本三级黄在线观看| 丁香欧美五月| 夜夜夜夜夜久久久久| 天天躁夜夜躁狠狠躁躁| 国产熟女午夜一区二区三区| 老司机靠b影院| 午夜福利在线观看吧| 欧美日韩瑟瑟在线播放| 亚洲国产精品一区二区三区在线| 国产免费男女视频| 国产伦人伦偷精品视频| 一本综合久久免费| 大陆偷拍与自拍| 亚洲 欧美一区二区三区| 精品乱码久久久久久99久播| 国产激情久久老熟女| 国产亚洲精品第一综合不卡| 十分钟在线观看高清视频www| 黑人巨大精品欧美一区二区蜜桃| 久久久精品国产亚洲av高清涩受| 久久欧美精品欧美久久欧美| 极品人妻少妇av视频| 国产欧美日韩一区二区三区在线| 国产色视频综合| 水蜜桃什么品种好| 国产一区二区三区在线臀色熟女 | 国产99白浆流出| 国产乱人伦免费视频| 国产蜜桃级精品一区二区三区| 老鸭窝网址在线观看| 性少妇av在线| 不卡av一区二区三区| 婷婷六月久久综合丁香| 成人黄色视频免费在线看| 一本综合久久免费| 国产精品国产av在线观看| 波多野结衣一区麻豆| 国产免费男女视频| 亚洲成人国产一区在线观看| 国产麻豆69| 成年版毛片免费区| 啦啦啦 在线观看视频| 大码成人一级视频| 亚洲精品在线美女| 久久久精品欧美日韩精品| 国产片内射在线| 亚洲伊人色综图| 高清黄色对白视频在线免费看| 欧美乱码精品一区二区三区| 免费观看人在逋| 好看av亚洲va欧美ⅴa在| 久久久久久大精品| 色播在线永久视频| 国产有黄有色有爽视频| 又黄又粗又硬又大视频| 狠狠狠狠99中文字幕| 两性午夜刺激爽爽歪歪视频在线观看 | 欧美日韩亚洲综合一区二区三区_| 久久伊人香网站| 老汉色∧v一级毛片| 免费高清在线观看日韩| 欧美中文日本在线观看视频| 亚洲欧美精品综合一区二区三区| 国产一区二区激情短视频| 精品久久蜜臀av无| 超碰97精品在线观看| 99国产精品一区二区蜜桃av| 精品国内亚洲2022精品成人| 搡老岳熟女国产| 国产精品成人在线| 午夜福利影视在线免费观看| 日韩欧美三级三区| 欧美黄色淫秽网站| 天堂俺去俺来也www色官网| 日本a在线网址| 亚洲精品久久午夜乱码| 久久久久久久午夜电影 | 狠狠狠狠99中文字幕| 欧美日韩瑟瑟在线播放| 免费人成视频x8x8入口观看| 麻豆成人av在线观看| 久久精品成人免费网站| 亚洲精品在线美女| 99热国产这里只有精品6| 在线观看www视频免费| 满18在线观看网站| 在线av久久热| 操美女的视频在线观看| 少妇 在线观看| 女性生殖器流出的白浆| 少妇的丰满在线观看| 亚洲av五月六月丁香网| 日日摸夜夜添夜夜添小说| 亚洲欧美日韩另类电影网站| 久久香蕉国产精品| 国产亚洲欧美精品永久| 最好的美女福利视频网| 欧美成狂野欧美在线观看| 一二三四在线观看免费中文在| 国产精品av久久久久免费| 成人精品一区二区免费| 国产精品免费一区二区三区在线| 十分钟在线观看高清视频www| 亚洲欧美日韩另类电影网站| 叶爱在线成人免费视频播放| 91老司机精品| 亚洲第一av免费看| aaaaa片日本免费| 亚洲精品中文字幕在线视频| 亚洲狠狠婷婷综合久久图片| 免费av中文字幕在线| 国产又爽黄色视频| 操美女的视频在线观看| 久久久久久人人人人人| 嫁个100分男人电影在线观看| 欧美乱色亚洲激情| 黄片小视频在线播放| 老司机午夜福利在线观看视频| 国产亚洲精品久久久久久毛片| 成人亚洲精品一区在线观看| 国产av一区在线观看免费| 色在线成人网| 欧美激情高清一区二区三区| 久久影院123| 婷婷精品国产亚洲av在线| 满18在线观看网站| 亚洲av成人一区二区三| 亚洲久久久国产精品| 午夜成年电影在线免费观看| 波多野结衣av一区二区av| 午夜精品久久久久久毛片777| 新久久久久国产一级毛片| 夜夜爽天天搞| 国产99白浆流出| 免费在线观看黄色视频的| ponron亚洲| 两人在一起打扑克的视频| 国产xxxxx性猛交| 在线播放国产精品三级| 国产欧美日韩精品亚洲av| 成人精品一区二区免费| а√天堂www在线а√下载| 手机成人av网站| 久久久久九九精品影院| 一进一出抽搐gif免费好疼 | 热re99久久精品国产66热6| 免费在线观看黄色视频的| 涩涩av久久男人的天堂| 午夜成年电影在线免费观看| 91精品三级在线观看| 色播在线永久视频| 久久久久久久精品吃奶| 丰满饥渴人妻一区二区三| 99热国产这里只有精品6| 村上凉子中文字幕在线| 高清在线国产一区| 国产一区二区在线av高清观看| 欧美日韩国产mv在线观看视频| 高清黄色对白视频在线免费看| 国产视频一区二区在线看| 国产欧美日韩一区二区精品| 亚洲美女黄片视频| 国产片内射在线| 成年人免费黄色播放视频| 香蕉久久夜色| 免费看十八禁软件| 999久久久国产精品视频| 日本vs欧美在线观看视频| 91成人精品电影| svipshipincom国产片| 午夜福利,免费看| 中文字幕最新亚洲高清| 亚洲视频免费观看视频| 我的亚洲天堂| 俄罗斯特黄特色一大片| 亚洲一区二区三区不卡视频| 欧美日韩亚洲综合一区二区三区_| 欧美乱色亚洲激情| a在线观看视频网站| 好男人电影高清在线观看| 久久草成人影院| 亚洲精品一二三| 国产精品野战在线观看 | 亚洲欧美日韩另类电影网站| 一进一出抽搐动态| av在线播放免费不卡| 91老司机精品| 中文字幕另类日韩欧美亚洲嫩草| 欧美成人午夜精品| 亚洲人成伊人成综合网2020| 久久精品国产亚洲av香蕉五月| 国产99久久九九免费精品| 中文字幕另类日韩欧美亚洲嫩草| 亚洲成人免费电影在线观看| 精品国产一区二区久久| 国产不卡一卡二| 精品久久久久久久久久免费视频 | 黑人欧美特级aaaaaa片| 国产av精品麻豆| 黄色成人免费大全| 在线观看日韩欧美| 国产精品久久久av美女十八| 国产精品一区二区免费欧美| 国产有黄有色有爽视频| 天堂俺去俺来也www色官网| 极品人妻少妇av视频| 婷婷六月久久综合丁香| 真人做人爱边吃奶动态| 电影成人av| 欧美一区二区精品小视频在线| 久久久久国产一级毛片高清牌| 亚洲男人天堂网一区| 国产亚洲精品一区二区www| 一边摸一边抽搐一进一小说| 乱人伦中国视频| 免费av中文字幕在线| av有码第一页| 亚洲av五月六月丁香网| 国产极品粉嫩免费观看在线| 精品国产一区二区三区四区第35| 国产99久久九九免费精品| а√天堂www在线а√下载| 妹子高潮喷水视频| 成年女人毛片免费观看观看9| 99热只有精品国产| 成人永久免费在线观看视频| 国产精华一区二区三区| 国产三级在线视频| 欧美久久黑人一区二区| 黄频高清免费视频| 身体一侧抽搐| 成人三级做爰电影| 19禁男女啪啪无遮挡网站| 亚洲一区中文字幕在线| 久99久视频精品免费| avwww免费| 久久国产亚洲av麻豆专区| 老鸭窝网址在线观看| 自线自在国产av| 国产精品永久免费网站| 国产一区二区三区在线臀色熟女 | 午夜老司机福利片| 国产精品国产av在线观看| 亚洲国产欧美网| 18禁裸乳无遮挡免费网站照片 | 色播在线永久视频| 又大又爽又粗| 色在线成人网| 高潮久久久久久久久久久不卡| 日本a在线网址| 国产高清视频在线播放一区| 法律面前人人平等表现在哪些方面| 国产成年人精品一区二区 | 天堂√8在线中文| 欧美在线一区亚洲| 欧美最黄视频在线播放免费 | 中国美女看黄片| 妹子高潮喷水视频| 国产国语露脸激情在线看| 好男人电影高清在线观看| 日本一区二区免费在线视频| 夜夜看夜夜爽夜夜摸 | 超色免费av| 精品少妇一区二区三区视频日本电影| 99国产精品一区二区蜜桃av| 91九色精品人成在线观看| 久久人人97超碰香蕉20202| 如日韩欧美国产精品一区二区三区| 午夜免费鲁丝| 久久精品影院6| 色播在线永久视频| 精品久久久久久久毛片微露脸| 日韩免费高清中文字幕av| 日本免费a在线| av免费在线观看网站| 99riav亚洲国产免费| 999久久久精品免费观看国产| 亚洲精华国产精华精| 国产一区二区三区视频了| 麻豆av在线久日| 黄网站色视频无遮挡免费观看| 麻豆av在线久日| 亚洲精品一卡2卡三卡4卡5卡| 中亚洲国语对白在线视频| 九色亚洲精品在线播放| 母亲3免费完整高清在线观看| 久久久久国产精品人妻aⅴ院| 天堂中文最新版在线下载| 久久精品亚洲精品国产色婷小说| 国产一区二区三区综合在线观看| 操出白浆在线播放| 亚洲伊人色综图| 女人精品久久久久毛片| 国产精品香港三级国产av潘金莲| 成人影院久久| 欧美黑人欧美精品刺激| 亚洲 欧美一区二区三区| 精品久久久久久久毛片微露脸| 91在线观看av| 精品久久久久久久毛片微露脸| 麻豆一二三区av精品| 久久久水蜜桃国产精品网| 在线观看免费高清a一片| 俄罗斯特黄特色一大片| 国产精品免费视频内射| 亚洲一卡2卡3卡4卡5卡精品中文|