Chemical Characterization and Anti-HIV-1 Activity Assessment of Iridoids and Flavonols from Scrophularia trifoliata

Plants are the everlasting source of a wide spectrum of specialized metabolites, characterized by wide variability in term of chemical structures and different biological properties such antiviral activity. In the search for novel antiviral agents against Human Immunodeficiency Virus type 1 (HIV-1) from plants, the phytochemical investigation of Scrophularia trifoliata L. led us to isolate and characterize four flavonols glycosides along with nine iridoid glycosides, two of them, 5 and 13, described for the first time. In the present study, we investigated, for the first time, the contents of a methanol extract of S. trifoliata leaves, in order to explore the potential antiviral activity against HIV-1. The antiviral activity was evaluated in biochemical assays for the inhibition of HIV-1Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) activity and HIV-1 Integrase (IN). Three isolated flavonoids, rutin, kaempferol-7-O-rhamnosyl-3-O-glucopyranoside, and kaempferol-3-O-glucopyranoside, 8–10, inhibited specifically the HIV-1 IN activity at submicromolar concentration, with the latter being the most potent, showing an IC50 value of 24 nM.

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Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.10.3123-3129.2003 ◽

2003 ◽

Vol 47 (10) ◽

pp. 3123-3129 ◽

Cited By ~ 256

Author(s):

Yasuhiro Koh ◽

Hirotomo Nakata ◽

Kenji Maeda ◽

Hiromi Ogata ◽

Geoffrey Bilcer ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitor ◽

Therapeutic Agent ◽

Close Contact ◽

Wide Spectrum ◽

Antiviral Agents ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC50], ∼0.003 μM; IC90, ∼0.009 μM) with minimal cytotoxicity (50% cytotoxic concentration for CD4+ MT-2 cells, 74 μM). UIC-94017 blocked the infectivity and replication of each of HIV-1NL4-3 variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 μM (IC50s, 0.003 to 0.029 μM), although it was less active against HIV-1NL4-3 variants selected for resistance to amprenavir (IC50, 0.22 μM). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections.

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Biological evaluation of molecules of the azaBINOL class as antiviral agents: Inhibition of HIV-1 RNase H activity by 7-isopropoxy-8-(naphth-1-yl)quinoline

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2019.06.044 ◽

2019 ◽

Vol 27 (16) ◽

pp. 3595-3604 ◽

Cited By ~ 1

Author(s):

Ross D. Overacker ◽

Somdev Banerjee ◽

George F. Neuhaus ◽

Selena Milicevic Sephton ◽

Alexander Herrmann ◽

...

Keyword(s):

Antiviral Agents ◽

Biological Evaluation ◽

Rnase H ◽

Hiv 1

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Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. Approaches Applicable to Epidemic HIV-1 Strains

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029300400403 ◽

1993 ◽

Vol 4 (4) ◽

pp. 207-214 ◽

Cited By ~ 6

Author(s):

A. R. Neurath ◽

N. Strick ◽

S. Jiang

Keyword(s):

Antiviral Activity ◽

North American ◽

Antiviral Agents ◽

Envelope Glycoproteins ◽

V3 Loop ◽

European North ◽

Consensus Peptide ◽

Antiviral Chemotherapy ◽

Anti Hiv ◽

Hiv 1

Several compounds, including the triphenylmethane derivative aurintricarboxylic acid (ATA) and porphyrins, were reported to inhibit the binding of anti-V3 loop-specific antibodies to the V3 loop of gp120 from HIV-1 III-B and to have antiviral activity, probably due to interference with the biological function of the V3 loop. However, these compounds can be applied to antiviral chemotherapy only if they interact with envelope glycoproteins from a multitude of epidemic HIV-1 strains and inhibit their replication. Since recombinant envelope glycoproteins, synthetic peptides and anti-V3 monoclonal antibodies may not be available for these HIV-1 strains, alternative assays are needed to prescreen different compounds for potential antiviral activity against these viruses. Results presented here indicate that: (1) virions of HIV-1 MN, most closely related to primary HIV-1 isolates from European and North American countries, and human anti-HIV-1 antibodies, can also be used for rapid prescreening of antiviral agents, (2) compounds with antiviral activity against HIV-1 MN, discerned by site-directed immunoassays, inhibited the reaction of human anti-HIV-1 with a V3 loop consensus peptide corresponding to European/North American HIV-1 isolates, and (3) meso-tetra (4-carboxyphenyl) porphine (MTCPP), one of the most potent inhibitors of HIV-1 replication selected on the basis of site-directed immunoassays, preferentially attached to the V3 loop of gp120.

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Biological Evaluation of Molecules of the azaBINOL Class as Antiviral Agents: Specific Inhibition of HIV-1 RNase H Activity by 7-Isopropoxy-8-(naphth-1-yl)quinoline

10.1101/525105 ◽

2019 ◽

Author(s):

Ross D. Overacker ◽

Somdev Banerjee ◽

George F. Neuhaus ◽

Selena Milicevic Sephton ◽

Alexander Herrmann ◽

...

Keyword(s):

Viral Entry ◽

Antiviral Agents ◽

Biological Evaluation ◽

Rnase H ◽

Synthetic Compounds ◽

Infectivity Assay ◽

Antiviral Compounds ◽

Specific Manner ◽

Drug Leads ◽

Hiv 1

AbstractInspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs in a singleround infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOLB#24), which exhibited low-micromolar activity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). Mode-of-action studies using a time-of-addition assay indicated that azaBINOLB#24acts after viral entry but before viral assembly and budding. HIV-1 reverse transcriptase (RT) assays that individually test for polymerase and RNase H activity were used to demonstrate thatB#24inhibits RNase H activity, most likely allosterically. Further binding analysis using bio-layer interferometry (BLI) showed thatB#24interacts with HIV-1 RT in a highly specific manner. These results indicate that azaBINOLB#24is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.

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A New Range of Chitosan Based Nano-antiviral Agents

Journal of Life Sciences ◽

10.31901/24566306.2021/13.1-2.259 ◽

2021 ◽

Vol 13 (1-2) ◽

Author(s):

Julio Garay-Jimenez

Keyword(s):

Antiviral Activity ◽

Antiviral Agents ◽

Coxsackie Virus ◽

Autoimmune Myocarditis ◽

Capture Assay ◽

Antigen Capture ◽

Immunodeficiency Virus ◽

P24 Antigen ◽

Syncytial Virus ◽

Hiv 1

ABSTRACT The current study involves the synthesis of fourteen analogs of oligochitosan and their screening for antiviral potential against human immunodeficiency virus (HIV), respiratory syncytial virus (RSV) and Coxsackie virus. The synthesized oligochitosan analogs were characterized by nuclear magnetic resonance (NMR) and FTIR techniques. HIV-1 p24 ELISA was performed using HIV-1 p24 antigen capture assay in order to estimate the viral infectivity loss. It was observed that sulfated oligochitosan was devoid of antiviral activity as compared to oligochitosan UN102 analog. The rest of UN102 analogs which include N-thiol (UN105), N-glutaryl (UN106), N-Azido (UN111) and N-phthaloyl (UN114) and N-citric analog (UN117) exhibited antiviral activity against HIV. The UN102 also decreased viral infection caused by RSV. In addition, UN102 was found to bind Coxsackie virus, which causes autoimmune myocarditis. The findings were of great interest to proceed for the development of novel antiviral agents.

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An Overview of Bioactive 1,3-Oxazole-Containing Alkaloids from Marine Organisms

Pharmaceuticals ◽

10.3390/ph14121274 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1274

Author(s):

Jinyun Chen ◽

Sunyan Lv ◽

Jia Liu ◽

Yanlei Yu ◽

Hong Wang ◽

...

Keyword(s):

Nitrogen Atom ◽

Chemical Synthesis ◽

Biological Activities ◽

Structural Features ◽

Biological Properties ◽

Therapeutic Agents ◽

Marine Organisms ◽

Chemical Structures ◽

First Time ◽

Oxazole Derivatives

1,3-Oxazole chemicals are a unique class of five-membered monocyclic heteroarenes, containing a nitrogen atom and an oxygen. These alkaloids have attracted extensive attention from medicinal chemists and pharmacologists owing to their diverse arrays of chemical structures and biological activities, and a series of 1,3-oxazole derivatives has been developed into therapeutic agents (e.g., almoxatone, befloxatone, cabotegravir, delpazolid, fenpipalone, haloxazolam, inavolisib). A growing amount of evidence indicates that marine organisms are one of important sources of 1,3-oxazole-containing alkaloids. To improve our knowledge regarding these marine-derived substances, as many as 285 compounds are summarized in this review, which, for the first time, highlights their sources, structural features and biological properties, as well as their biosynthesis and chemical synthesis. Perspective for the future discovery of new 1,3-oxazole compounds from marine organisms is also provided.

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Antiviral activities of pyridine fused and pyridine containing heterocycles, a review (From 2000 to 2020)

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210126143558 ◽

2021 ◽

Vol 21 ◽

Author(s):

Seyedeh Roya Alizadeh ◽

Mohammad Ali Ebrahimzadeh

Keyword(s):

Antiviral Activity ◽

Biological Activities ◽

Critical Role ◽

Antiviral Agents ◽

Rnase H ◽

Pyridine Derivatives ◽

Action Mechanism ◽

Syncytial Virus

: Heterocyclic compounds play a critical role in medicinal chemistry and many available drugs contain heterocyclic rings. A six-membered heterocyclic compound pyridine showed various applications that acts as an important solvent, reagent, and precursor in agrochemicals and pharmaceuticals. Due to the increase of drug resistance, there is an obvious medical need to develop new antiviral agents. Various derivatives of pyridine scaffold display abroad biological activities such as anti-microbial, anti-viral, antioxidant, anti-diabetic, anti-cancer, anti-malaria, analgesic and anti-inflammatory activities, psychopharmacological antagonistic, anti-amoebic agents, and anti-thrombic activity. Due to the high importance of pyridine derivatives, in the present review, we tried to collect and classify many pyridine derivatives based on their structures from 2000 to 2020. Pyridine derivatives were classified into two general categories including pyridine containing heterocycles and pyridine fused rings. Structure-activity relationship (SAR) and the action mechanism of derivatives were also investigated. According to the recent studies, these derivatives exhibited good antiviral activity against different types of viruses such as the human immunodeficiency viruses (HIV), the hepatitis C virus (HCV), the hepatitis B virus (HBV), Respiratory syncytial virus (RSV), and Cytomegalovirus (CMV). These derivatives inhibited viral application with different action mechanism such as RT inhibition, polymerase inhibition, Inhibition of RNase H activity, inhibition of maturation, inhibition of the viral thymidine kinase, AAK1 (Adaptor-Associated Kinase 1) inhibition, GAK (Cyclin G-associated kinase) inhibition, inhibition of post-integrational event, inhibition of HDAC6, CCR5 antagonistic activity, DNA and RNA replication inhibition, gene expression inhibition, cellular NF-jB signaling pathway and neuraminidase (NA) inhibition, protein synthesis inhibition, and generally inhibition of viral replication cycle. This paper summarily expressed the past and present results about the discovery of novel lead compounds with good antiviral activity. Studies exhibited that almost all of the evaluations were performed by way of in vitro testing and is necessary to investigate in vivo and clinical testing for having better evaluations in the future. We believe that pyridine derivatives can be used as promising antiviral agents and needs to perform more broad investigations in this field.

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4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.5.1539-1546.2001 ◽

2001 ◽

Vol 45 (5) ◽

pp. 1539-1546 ◽

Cited By ~ 99

Author(s):

Ei-Ichi Kodama ◽

Satoru Kohgo ◽

Kenji Kitano ◽

Haruhiko Machida ◽

Hiroyuki Gatanaga ◽

...

Keyword(s):

Antiviral Activity ◽

Reverse Transcriptase ◽

Wide Spectrum ◽

Nucleoside Analogs ◽

Transcriptase Inhibitor ◽

Multidrug Resistant ◽

Human Immunodeficiency Viruses ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1

ABSTRACT A series of 4′-ethynyl (4′-E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4′-E-2′-deoxycytidine (4′-E-dC), 4′-E-2′-deoxyadenosine (4′-E-dA), 4′-E-2′-deoxyribofuranosyl-2,6-diaminopurine, and 4′-E-2′-deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 μM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4′-E analogs also suppressed replication of various drug-resistant HIV-1 clones, including HIV-1M41L/T215Y, HIV-1K65R, HIV-1L74V, HIV-1M41L/T69S-S-G/T215Y, and HIV-1A62V/V75I/F77L/F116Y/Q151M. Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4′-E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1Y181C, and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4′-E-thymidine and 4′-E-dC was blocked by the addition of thymidine and 2′-deoxycytidine, respectively, while that of 4′-E-dA was not affected by 2′-deoxyadenosine, similar to the antiviral activity reversion feature of 2′,3′-dideoxynucleosides, strongly suggesting that 4′-Eanalogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4′-E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.

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Evaluating the Effect of Amine-geldanamycin Hybrids on Antiviral Activity against Influenza Virus

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i22b31400 ◽

2021 ◽

pp. 71-82

Author(s):

Thongchai Taechowisan ◽

Tipparat Samsawat ◽

Chanjira Jaramornburapong ◽

Weerachai Phutdhawong ◽

Waya S. Phutdhawong

Keyword(s):

Influenza Virus ◽

Molecular Docking ◽

Antiviral Activity ◽

Binding Free Energy ◽

Antiviral Agents ◽

Biological Properties ◽

Virus Propagation ◽

Cytotoxicity Activity ◽

Ic50 Values ◽

Chicken Eggs

Aims: The purpose of this study was to synthesis novel amine-geldanamycin hybrids (AGH) and evaluate their biological properties. Study Design: Experimental study. Place and Duration of Study: The study was carried out at the Department of Microbiology and Department of Chemistry, Faculty of Science, Silpakorn University, from December 2019 - November 2020. Methodology: Three new amine-geldanamycin hybrids (AGH); compounds 2 to 4 were synthesised by nucleophilic substitution of geldanamycin (1). The solubility, cytotoxicity, antiviral activity and molecular docking analyses were carried out. Results: The solubility of AGH in water was 1.918-5.571 mM, higher than that of compound 1. Compound 2 exhibited weak cytotoxicity activity against Vero and LLC-MK2 cells, with IC50 values of 229.19 and 330.58 µg/ml, respectively. All compounds inhibited influenza virus propagation in embryonated chicken eggs at the lowest amount of 1.25 µg per egg. They interacted positively with Hsp90, showing a binding free energy (DG) of -112.00 to -116.34 kcal/mol, which indicated lower Hsp90 affinity compared with that of geldanamycin (-133.06 kcal/mol) and 17-dimethylamino ethylamino-17-demethoxygeldanamycin (-136.55 kcal/mol), despite being bound in the similar active site. For the viral absorption, only AGH inhibited hemagglutination at a concentration of 25 µg/ml. Conclusion: The study findings revealed, through molecular docking analysis, that the development of AGH improved the antiviral activity. The AGH inhibited not only influenza virus propagation, but also viral absorption. Therefore, AGH could be considered a new choice for antiviral agents.

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(Z)- and (E)-2-(Hydroxymethylcyclopropylidene)-Methylpurines and Pyrimidines as Antiviral Agents

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029800900406 ◽

1998 ◽

Vol 9 (4) ◽

pp. 57-68 ◽

Cited By ~ 27

Author(s):

Y-L Qiu ◽

RG Ptak ◽

JM Breitenbach ◽

J-S Lin ◽

Y-C Cheng ◽

...

Keyword(s):

Antiviral Activity ◽

Antiviral Agents ◽

Human Herpesvirus ◽

Murine Cytomegalovirus ◽

Strong Inhibitor ◽

Varicella Zoster ◽

Daudi Cells ◽

Hiv 1 ◽

Hsv 1

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and evaluated for antiviral activity. Reaction of the Z- and E-2-amino-6-chloropurine methylenecyclopropanes with ammonia or cyclopropylamine gave 2,6-diamino or 2-amino-6-cyclopropylamino analogues. Alkylation elimination of N4-acetylcytosine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave a mixture of the Z-and E-methylenecyclopropane derivatives of cytosine. Reduction furnished a mixture of syncytol and the E isomer. Benzoylation led to the respective N4-benzoyl derivatives which were separated by chromatography. Debenzoylation afforded pure syncytol and the E isomer. Alkylation of 2,4-bis-O-trimethylsilylthymine with ethyl Z- and E-2-bromo-2-bromomethylcyclopropane-1-carboxylates gave the corresponding Z- and E-1-bromo-cyclopropylmethylderivatives of thymine. Base-catalysed elimination of HBr gave Z- and E-methylenecyclopropane carboxylic esters. Reduction furnished, after chromatographic separation, synthymol and the E isomer. The Z/E isomeric assignment of the obtained products followed from 1H NMR spectroscopy. The methylenecyclopropane analogues were tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4–2 μM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4–29 and 11–24 μM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 μM). Syncytol was the most potent against EBV (EC50 <0.41 and 2.5 μM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 μM) and the Z-2-amino-6-cyclopropylaminopurine derivative (EC50 11.8 μM). Syncytol was also most effective against VZV (EC50 3.6 μM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 μM against HSV-1 (ELISA) and 1.3 μM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and >74 μM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 μM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.

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