Design, synthesis and biological activity of DB02 amino acid derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors / 药学学报

To improve the stability of amino acid ester derivatives of DB02, a series of 24 amide derivatives of DB02 amino acids as non-nucleoside HIV-1 reverse transcriptase inhibitor were designed and synthesized based on bioisosterism by replacing amino acid ester scaffold with more stable amide bond. The anti-HIV-1 activity of these compounds was evaluated by MTT assay and counting the number of syncytia. Most of the target compounds showed a potential anti-HIV-1 activity, among which compounds 2d, 2i, 2l, 2s, and 2w had better antiviral effect than lead compound DB02, with a therapeutic index > 1 000.00. Finally, the structure-activity relationship of these compounds was discussed, which provided new ideas for the further development of DB02 derivatives.

Challenges in integrating component level technology and system level information from Ayurveda: Insights from NMR phytometabolomics and anti-HIV potential of select Ayurvedic medicinal plants

Background: Information from Ayurveda meeting the analytical challenges of modern technology is anarea of immense relevance. Apart from the cerebral task of bringing together two different viewpoints,the question at the pragmatic level remains ‘who benefits whom’.Objective: The aim is to highlight the challenges in integration of information (Ayurvedic) and technology using test examples of Nuclear Magnetic Resonance (NMR) metabolomics and anti-HIV-1 potential of select Ayurvedic medicinal plants. The other value added objective is implications andrelevance of such work for Ayurveda.Materials and methods: Six medicinal plants (Azadirachta indica, Tinospora cordifolia, Swertia chirata,Terminalia bellerica, Zingiber officinale and Symplocos racemosa) were studied using high resolutionproton NMR spectroscopy based metabolomics and also evaluated for anti-HIV-1 activity on threepseudoviruses (ZM53 M.PB12, ZM109F.PB4, RHPA 4259.7).Results: Of the six plants, T. bellerica and Z. officinale showed minimum cell cytotoxicity and maximumanti-HIV-1 potential. T. bellerica was effective against all the three HIV-1 pseudoviruses. Untargeted NMRprofiling and multivariate analyses demonstrated that the six plants, all of which had different Ayurvedicpharmacological properties, showed maximum differences in the aromatic region of the spectra.Conclusion: The work adds onto the list of potential plants for anti-HIV-1 drug molecules. At the sametime, it has drawn attention to the different perspectives of Ayurveda and Western medicine underscoring the inherent limitations of conceptual bilinguism between the two systems, especially in thecontext of medicinal plants. The study has also highlighted the potential of NMR metabolomics in studyof plant extracts as used in Ayurveda.© 2017 Transdisciplinary University, Bangalore and World Ayurveda Foundation. Publishing Services byElsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Anti-HIV lignans from Justicia procumbens / 中国天然药物

Twenty-one lignans including three new ones (1, 2 and 13) were isolated from Justicia procumbens. The chemical structures of the new lignans were determined by spectroscopic means including 1D and 2D NMR analysis. These compounds were evaluated for their cytotoxic and anti-HIV activities. The new secoisolariciresinol dimethyl ether acetate (13) exhibited anti-HIV-1 activity with an IC value of 5.27 μmol·L and a selective index (SI) value of 2.2. The known arylnaphthalene lignan procumbenoside A (3) and diphyllin (8) demonstrated inhibitory activity against HIV-1 with IC values of 4.95 (SI > 6.2) and 0.38 μmol·L (SI = 5.3), respectively.

Design,Synthesis and Anti-HIV-1 Activity Evaluation of N-Benzamide Derivatives / 中国药学杂志

OBJECTIVE: To design and synthesize HIV-1 Vif inhibitor RN-18 derivatives and investigate their antiviral activities. METHODS: RN-18 was used as the lead compound, and optimizations were carried out on the two side chains and the middle benzene ring. The anti-HIV-1 activities of the target compounds were analyzed by p24 assay, and the cytotoxicities of compounds with better activities were tested with MTT method. RESULTS: Twenty-eight new derivatives were prepared, and their structures were characterized by MS and 1H-NMR. The activity test showed that the antiviral activities of seven compounds were obviously improved, and the activity of compound 26 was increased to be 11 times higher than that of RN-18, with an EC50 value of 21.8 μmol·L-1. CONCLUSION: Replacing the middle benzene ring of RN-18 with heterocycles generally improves the anti-HIV-1 activity, which provides the basis for further study.

Lignans chemical constituents from Diaphragma Juglandis Fructus and activity of inhibiting HIV / 中草药

Objective To study the lignans chemical constituents from Diaphragma Juglandis Fructus and their activity of inhibiting HIV. Methods The constituents were isolated from Diaphragma Juglandis Fructus and purified by column chromatography, and the structures were identified by spectra analysis and chemical methods.The activity of anti-HIV-1 were detected by LEDGF/p75-IN proteins complex ELISA kit. Results Sixteen compounds were isolated from Diaphragma Juglandis Fructus and the structures were identified as (-)-syringaresinol (1), (+)-pinoresinol (2), (+)-(7R,7’R,7″S,7’’’S,8S,8’S,8″S,8’’’S)-4″,4’’’-dihydroxy-3,3’,3″,3’’’,5,5’- hexamethoxy-7,9’;7’,9-diepoxy-4,8″;4’,8’’’-bisoxy-8,8’-dineolignan-7″,7’’’,9″,9’’’-tetraol (3), 2,3-dihydroxy-1-(4’-hydroxy-3’-methoxy- phenyl)-propan-1-one (4), 3-hydroxy-1-(4’-hydroxy-3’-methoxyphenyl)-propan-1-one (5), 3’,4’-dimethoxyphenylpropanediol (6), (2S)-3,3-di-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol (7), 3-hydroxy-1-(4’-hydroxy-3’,5’-dimethoxy phenyl)-propan-1-one (8), (1R,5R,6R)-6-{4’-O-[8″-(7″-(4″-hydroxy-3″-methoxyphenyl)) glyceol]-3’,5’-dimethoxyphenyl}-3,7-dioxabicyclo [3.3.0] octan-2-one (9), curcasinlignan B (10), evofolin-B (11), (7S,8R)-dihydrodehydrodiconiferyl alcohol (12), pinnatifidanin C I (13), (+)-(7S,8S)-4,1’-dihydroxy-3,3’,5’-trimethoxy-7,8,9-trinor-8,4’-oxyneolignan-7,9-diol (14), dysosmarol (15), and 1-(4’-hydroxy-3’-methoxyphenyl)-2- [4″-(3-hydroxypropyl)-2″,6″-dimethoxyphenoxy]-propane-1,3-diol (16). Conclusion All compounds are isolated from Diaphragma Juglandis Fructus for the first time. Compound 13 has the potential activity of inhibiting HIV-1.

Discovery of N-arylsulfonyl-3-acylindole benzoyl hydrazone derivatives as anti-HIV-1 agents

The discovery and development of novel inhibitors with activity against variants of human immunodeficiency virus type 1 (HIV-1) is pivotal for overcoming treatment failure. As our ongoing work on research of anti-HIV-1 inhibitors, 32 N-arylsulfonyl-3-acylindole benzoyl hydrazone derivatives were prepared by introduction of the hydrazone fragments on the N-arylsulfonyl-3-acylindolyl skeleton and preliminarily screened in vitro as HIV-1 inhibitors for the first time. Among of all the reported analogues, eight compounds exhibited significant anti-HIV-1 activity, especially N-(3-nitro)phenylsulfonyl-3-acetylindole benzoyl hydrazone (18) and N-(3-nitro)phenylsulfonyl-3-acetyl-6-methylindole benzoyl hydrazone (23) displayed the most potent anti-HIV-1 activity with EC50 values of 0.26 and 0.31 µg/mL, and TI values of >769.23 and >645.16, respectively. It is noteworthy that introduction of R3 as the methyl group and R2 as the hydrogen group could result in more potent compounds. This suggested that introduction of R3 as the methyl group could be taken into account for further preparation of these kinds of compounds as anti-HIV-1 agents

Synthesis and Anti-HIV-1 Activity of One Schiff Base Derivative with Glucosamine of Gossypol / 中国药师

Objective: To confirm the structure and preferential conformation of the Schiff base of gossypol with 1, 3, 4, 6-tetra-O-acetyl-β-D-glucosamine and explore its anti-HIV-1 activity.Methods: The Schiff base of gossypol with 11, 3, 4, 6-tetra-O-acetyl-β-D-glucosamine was synthesized and identified by FT-IR, NMR spectroscopy and the PM6 semi-classical calculation.The inhibitory activity of the novel compound against the laboratory-adapted HIV-1IIIB strain was examined using the HIV-1IIIB/TZM-bl indicator cell culture system.Results: The 1H and 13C-NMR signals of the new Schiff base were assigned.The PM6 semi-classical calculation indicated that enamine-enamine tautomeric form of the new Schiff base was more stable,which was stabilized by the intramolecular hydrogen bonds.The anti-HIV-1 test showed that the compound could block the entry of HIV-1IIIB into the target cells.Conclusion: The Schiff base of gossypol with 1, 3, 4, 6-tetra-O-acetyl-β-D-glucosamine exhibits enamine-enamine tautomeric form in solution, which shows potential anti-HIV-1 activity.

Diterpenes from stem bark of Euphorbia neriifolia / 中草药

Objective To investigate the diterpenes from the stem bark of Euphorbia neriifolia L. and their anti-HIV-1 activity. Methods The chemical constituents were isolated and purified by column chromatography over silica gel, ODS, MCI CHP-20P, Sephadex LH-20, and preparative HPLC. Their structures were identified by the analysis of their physicochemical properties and the spectral data of NMR and MS. The anti-HIV-1 activity of the compounds was tested by cell detection models established by HIV-1 NL4-3 infected MT-4 cells. Results Nine compounds were isolated from the stem bark of the plant, namely 12α-acetoxy- 3β,7α-dihydroxy-8α-methoxyingol (1), 3β,8α,12α-triacetoxy-7α-benzoyloxyingol (2), 3β,8α,12α-triacetoxy-7α-tigloyloxyingol (3), ent-3-oxoatis-16α,17-acetonide (4), 13β-hydroxy-3,15-dioxoatis-16-ene (5), ent-3β,(13S)-dihydroxyatis-16-en-14-one (6), atis-16- en-14-oxo-3β,13(S)-diol (7), ent-(13S),18-dihydroxyatis-16-ene-3,14-dione (8), 4,13β-dihydroxy-14-oxo-3,4-secoatis-16-en-3-oic acid methyl ester (9). Conclusion Compound 1 is a new natural product. Compounds 2-4, and 6-8 are isolated from the plant for the first time. Furthermore, compound 4 exhibited moderate anti-HIV-1 activities, with EC50 values of 8.7 μg/mL (SI = 1.92).

The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro / 药学学报

To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC50 greater than 200 μg·mL-1. DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1IIIB, HIV-174V, HIV-1RF/V82F/184V, HIV-1NL4-3 gp41(36G) N42S, HIV-1KM018, HIV-1TC-1 and HIV-1Wan. However, NNRTIs drug-resistant strain HIV-1A17 showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.

Advances in studies on HIV-1 multi-target drugs from natural products / 中草药

During the curing of complex disease, prospective therapeutic effect has been more and more difficult to achieve by using single-target inhibitors. Along with the development of systems biology and network pharmacology, the nosogenesis and the pathological process have been studied in depth, and people find that multi-target inhibitors can overcome many defects by using single-target inhibitors. Multi-target inhibitors include multicomponent and single component, but single component takes more advantages. The treatment of AIDS is a world problem, single-target inhibitors and multicomponent multi-target inhibitors (i.e. HAART) are used; However, viral height variability and severe drug resistance restrict the wide application of the two therapeutics. Therefore, the single component multi-target inhibitors with low toxicity and highperformance have been the most important choice to treat AIDS caused by HIV-1. The single component multi-target HIV-1 inhibitors mostly come from rational drug design and screening. Some HIV-1 inhibitors have been discovered from the natural products which have extensive sources and wide variety of kinds. That is an important way to develop lead compounds of HIV-1 inhibitors. This paper summarizes the advances in studies on HIV-1 multi-target drugs from natural products.

Anti HIV-1 Activity of the Crude Extracts of Guaiacum officinale L. (Zygophyllaceae).

Aim: Jamaica is rich in medicinal plants. Guaiacum officinale is the “National Flower”, with reported uses in folk medicine for the treatment of various conditions including inflammation. In our search for plants with anticancer and anti-infective properties, we evaluated Guaiacum officinale for activity against HIV-1. Methodology: The leaf, seed and twig extracts of G. officinale were screened for anti HIV-1 properties in primary peripheral blood mononuclear cells (PBMCs) infected with the reference HIV-1 BaL strain. Results: All the tested extracts inhibited HIV-1 p24 production by infected cells, with EC50 concentrations of 22.35μg/ml, 23.42μg/ml and 25.04μg/ml, respectively for the leaf, seed and twig extracts. As comparison, Betulinic acid had an EC50 value of 27.50μg/ml. The tested extracts had IC50/EC50 selectivity index (SI) values of ≥ 3, which compared favorably to Betulinic acid SI value of 1.09. Conclusion: The results of this study suggest that extracts of G. officinale may provide leads for the discovery of new drug agents against HIV-1.

Ellagic acid & gallic acid from Lagerstroemia speciosa L. inhibit HIV-1 infection through inhibition of HIV-1 protease & reverse transcriptase activity.

Background & objectives: Banaba (Lagerstroemia speciosa L.) extracts have been used as traditional medicines and are effective in controlling diabetes and obesity. The aim of this study was to evaluate the anti-HIV property of the extracts prepared from the leaves and stems of banaba, and further purification and characterization of the active components. Methods: Aqueous and 50 per cent ethanolic extracts were prepared from leaves and stems of banaba and were evaluated for cytotoxicity and anti-HIV activity using in vitro reporter gene based assays. Further, three compounds were isolated from the 50 per cent ethanolic extract of banaba leaves using silica gel column chromatography and characterization done by HPLC, NMR and MS analysis. To delineate the mode of action of the active compounds, reverse transcriptase assay and protease assay were performed using commercially available kits. Results: All the extracts showed a dose dependent inhibition of HIV-1-infection in TZM-bl and CEM-GFP cell lines with a maximum from the 50 per cent ethanolic extract from leaves (IC50 = 1 to 25 μg/ml). This observation was confirmed by the virus load (p24) estimation in infected CEM-GFP cells when treated with the extracts. Gallic acid showed an inhibition in reverse transcriptase whereas ellagic acid inhibited the HIV-1 protease activity. Interpretation & conclusions: The present study shows a novel anti-HIV activity of banaba. The active components responsible for anti-HIV activity were gallic acid and ellagic acid, through inhibition of reverse transcriptase and HIV protease, respectively and hence could be regarded as promising candidates for the development of topical anti-HIV-1 agents.

HIV-1 integrase inhibitory activity of endophytic fungi from Aquilaria sinensis (Lour.) Gilg / 中国药学杂志

OBJECTIVE: To investigate the HIV-1 integrase inhibitory activity of endophytic fungi from medicinal plant Aquilaria sinensis (Lour.) Gilg. METHODS: HIV-1 integrase inhibitory activity of the isolated endophytic fungi was determined by HIV-1 integrase strand transfer inhibitory activity assay, and the active metabolites of the endophytic fungi with the greatest potential were studied by activity tracking. RESULTS: Among 78 strains of endophytic fungi isolated from A. sinensis, nine strains (11.54%) showed strong inhibitory activity against HIV-1 integrase. Three compounds were obtained from the fermentation of strain HN-AS-8 which was identified to be Chaetomium globosum by HIV-1 integrase strand reaction. Compound 1 inhibited HIV-1 integrase with IC50 value of 35.4 μmol · L-1, and compounds 1 and 3 were for the first time isolated from Chaetomium sp. CONCLUSION: Potential anti-HIV-1 metabolites exist in the endophytic fungi from A. sinensis, which can be new resources for new anti-AIDS drugs.

Evaluation of a simultaneous HIV antigen and antibody detection test in Korean population

Current diagnosis of human immunodeficiency virus (HIV) infection relies on the detection of anti-HIV antibodies by enzyme-linked immunosorbent assay (ELISA). Recently, kits detecting both p24 antigenemia and anti-HIV/anti-HIV2 antibodies have been developed. Thus, it is necessary to compare those kits developed as such. The aim of this study was to evaluate the diagnostic efficiency of a simultaneous detection test of p24 antigen and anti-HIV1/2 antibodies in a low prevalence area. Eight hundred and four randomly selected sera proven negative for HIV infection and 110 sera from 54 patients diagnosed as HIV infected, obtained between 1999 and 2000, were used for this study. One commercial lot of panels composed of consecutive sera obtained from known HIV-infected patient was included. Anti-HIV1/2 antibodies were detected by two different commercial ELISA kits, one from Korean and the other from German manufacturer. P24 antigen test was performed by ELISA. The simultaneous HIV antigen and antibody detection test was carried out. In the meantime, HIV RNA PCR and anti-HIV and anti-HIV2 western blot assays were also performed to confirm the test results in cases the test results didn't agree. The simultaneous detection kit showed 100% sensitivity and 99.6% specificity. Furthermore, the test displayed the possibility of earlier diagnosis than conventional anti-HIV1/2 ELISA with the results obtained from a group of consecutive panel sera infected with HIV. From these results, we concluded that the simultaneous HIV antigen and antibody detection test can be applied as a substitute clinical screening test in the place of conventional anti-HIV1/2 ELISA, and there is the probable benefit of early diagnosis.

Evaluation of a Screening Test kit of Simultaneous p24 Antigen and Anti-HIV1/2 Detection in Diagnostic Aspect / 대한임상병리학회지

BACKGROUND: Human immunodeficiency virus(HIV) is the causative agent of acquired immune deficiency syndrome(AIDS). Current diagnosis of HIV infection relies on the detection of anti-HIV antibodies by ELISA. Recently, simultaneous detection kit of p24 antigenemia and anti-HIV1/anti-HIV2 antibodies were developed. The aim of this study was to evaluate the diagnostic kit of simultaneous detection with p24 antigen and anti-HIV1/2 in diagnostic aspect. METHODS: Eight hundred and four sera which were obtained between July 1999 and August 1999 and 110 sera from 54 patients diagnosed as HIV infection were included. One lot of panels composed of consecutive sera obtained from known HIV-infected patients was included. The detection of anti-HIV1/2 antibodies was done by Genedia HIV1/2 ELISA 3.0 kit(Greencross, Seoul, Korea) and Enzygnost anti-HIV1/2 Plus(Behringwerke, Marburg, Germany). The simultaneous detection of p24 antigenemia and anti-HIV1/2 antibodies was done with VIDAS DUO kit(bioMerieux, Lyon, France). The Vironostika HIV-1 antigen kit was used for detection of p24 antigen. The HIV RNA PCR and anti-HIV western blot assay were also performed to confirm the test results in discrepant cases. RESULTS: The simultaneous detection kit showed 100% sensitivity and 99.6% specificity. The possibility of earlier diagnosis than conventional anti-HIV1/2 EIA was also suggested by the results obtained with a group of consecutive panel sera infected with HIV. CONCLUSION: The simultaneous p24 antigen and anti-HIV1/2 detectin kit can be applied as a clinical screening test as a substitution of conventional anti-HIV1/2 EIA, and there is a probable gain especially in early diagnosis.

Interferência da riboflvina (vit. B2) nas análises fluorométricas modernas (relato de 3 casos): nota prévia / Interference of the riboflavin in the fluorometric analysis

A emissão de forte fluorescência da riboflavina (vit. 82) pode interferir nas análises fluorimétricas qualitativas fornecendo resultados falso-positivos nos exames sorológicos, após ingestão de polivitamínicos (relato de 3 casos).