Synthesis of anti-HIV nucleoside conjugates with lipophilic diol compounds

Synthesis of anti-HIV nucleoside lipophilic derivatives with diol compounds in which two antiviral pharmacophore residues are linked by a single hydrophobic fragment is described. It is suggested to use 2,3,4,5-tetra-O-benzyl-D, L-iditol and 1,12-dodecanediol as hydrophobic transport systems. Succinic and phosphodiester fragments were used for binding molecular units in the target conjugates. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 5, pp. 41–45, May, 2006.     

Study of the Effects on DNA of Two Novel Nucleoside Derivatives Synthesized as Potential Anti-HIV Agents

The pursuit of antiviral active compounds against different classes of viruses, in particular HIV, HBV, and HTLV is an area of important and intense research. In the current study, two novel nucleoside derivatives belonging to a new class of isoxazolidine were successfully synthesized as potential anti-HIV agents by replacement of the furanose ring by a N,O-heterocyclic ring Both compounds were investigated for biological activity, namely, mutagenic and antimutagenic properties. Using Salmonella typhimurium strains TA97, TA100, and TA102, both compounds proved to be nonmutagenic, which may be considered an encouraging result to further elucidate other biological activities. Antimutagenic testing of the synthesized compounds revealed that they are active against the base-pair substitution mutagen sodium azide. However, they did not show any indication as antimutagenic agents against hydrogen peroxide and mitomycin C (oxidative mutagens) or against nitrophenylenediamine (a base-pair substitution and frameshift mutagen). Structure–activity relationship is also discussed. Testing these compounds as antiviral agents is highly recommended.     

Exploration of imidazole and imidazopyridine dimers as anticancer agents: Design,synthesis, and structure–activity relationship study

Dimerization of proteins/receptors plays a critical role in various cellular processes, including cell proliferation and differentiation. Therefore, targeting such dimeric proteins/receptors by dimeric small molecules could be a potential therapeutic approach to treating various diseases, including inflammation‐associated diseases like cancer. A novel series of bis‐imidazoles ( 13–18 ) and bis‐imidazo[1,2‐a]pyridines ( 19–28 ) were designed and synthesized from Schiff base dimers ( 1–12 ) for their anticancer activities. All the synthesized compounds were screened for anticancer activities against three cancer cell lines, including cervical (HeLa), breast (MDA‐MB‐231), and renal cancer (ACHN). From structure–activity relationship studies, imidazo[1,2‐a]pyridines ( 19–28 ) showed remarkable cytotoxic activities, with compounds 19 and 24 showing the best inhibitory activities against all three cell lines. Especially, both 19 and 24 were very effective against the breast cancer cell line ( 19 , GI₅₀ = 0.43 µM; 24 , GI₅₀ = 0.3 µM), exceeding the activity of the control adriamycin (GI₅₀ = 0.51 µM). The in vivo anticancer activity results of compounds 19 and 24 were comparable with those of the animals treated with the standard drug tamoxifen. Therefore, the dimeric imidazo[1,2‐a]pyridine scaffold could serve as a potential lead for the development of novel anticancer agents.     

Synthesis and antiviral activity of phosphoralaninate derivatives of methylenecyclopropane analogues of nucleosides.

Phenylmethylphosphoro-L-alaninate prodrugs of antiviral Z-methylenecyclopropane nucleoside analogues and their inactive E-isomers were synthesized and evaluated for their antiviral activity against HCMV, HSV-1, HSV-2, HHV-6, EBV, VZV, HIV-1 and HBV. The adenine Z-analogue was a potent inhibitor of all these viruses but it displayed cellular toxicity. The guanine Z-derivative was active against HCMV, HBV, EBV and VZV and it was not cytotoxic. The 2,6-diaminopurine analogue was the most potent against HIV-1 and HBV and somewhat less against HHV-6, HCMV, EBV and VZV in a non-cytotoxic concentration range. The 2-amino-6-cyclopropylamino and 2-amino-6-methoxypurine prodrugs were also more active than parent analogues against several viruses but with a less favorable cytotoxicity profile. In the E-series of analogues, adenine derivative was active against HIV-1, HBV and EBV, and it was non-cytotoxic. The guanine analogue exhibited a significant effect only against HBV. The 2,6-diaminopurine E-analogue was inactive with the exception of a single EBV assay. The 2-amino-6-methoxypurine Z-methylenecyclopropane nucleoside analogue was an effective inhibitor of HCMV, MCMV and EBV. The 2,6-diaminopurine Z-prodrug seems to be the best candidate for further development.     

Synthesis of some new substituted thiosemicarbazides as potential antiviral agents

The substituted thiosemicarbazides 1–15 , synthesized by the condensation of substituted 5-chloro-diphenylamine-2-carboxylic acid hydrazides with appropriate arylisothiocyanates, have been tested for their antiviral activity against the plant virus, sunnhemp rosette virus, in vitro as well as in vivo and against the animal virus, ranikhet disease virus, in a stationary culture of chorioallantoic membranes of chick embryo. The majority of these compounds showed significant antiviral activity against both viruses. The structure-activity relationships have further been studied and are discussed.     

Synthesis and biological evaluation of 9-[2-fluoro-4-hydroxy-3-hydroxymethyl-2-butenyl]adenine and its related compounds as open-chain analogues of neplanocin A

Novel 9-[2-fluoro-4-hydroxy-3-hydroxymethyl-2-butenyl]adenine and its related compounds were designed and synthesized as open-chain analogues of neplanocin A. Alkylation of adenine or pyrimidine bases with the mesylate4 was chosen as a simple approach to the synthesis of 2-fluoro-2-butenylated nucleosides. Mesylate4 was prepared from dihydroxyacetone dimervia four steps in 58% overall yield. The synthesized compounds were evaluated their antiviral activity against HSV, HIV and Polio viruses.     

(+/-)-3-Allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepin, a new high-affinity D1 dopamine receptor ligand: synthesis and structure-activity relationship.

The 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines form a series of compounds having a high affinity at the D1 dopamine receptor. The 6-chloro derivative has been previously shown to have enhanced affinity, selectivity, and agonist activity. In an attempt to study the effect of substitution of a 6-bromo group in place of the 6-chloro, we have synthesized a series of compounds and evaluated them for their affinity for the D1 receptor. The results show that the 6-bromo derivatives have virtually identical affinities to their 6-chloro counterparts, a finding similar to that found in the D1 antagonist 7-halo-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine series. From the present work, 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (6-Br-APB) has been identified as a suitable candidate for further in vivo studies and resolution into its active and inactive enantiomers.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

Quantitative Structure–Activity Relationship (QSAR) Analysis of the Cytotoxicities Of Aminohydroxyguanidine Derivatives and Their Antiviral Activities in Vitro

Substituted Schiff bases of l-amino-3-hydroxyguanidine (SB-HAG) were tested for the first time against noninfected T4 lymphocytes (CEM-6 cells) and the same cell line infected by HIV-1 in vitro. Twenty-one of 23 compounds at micromolar levels did not inhibit the growth of the noninfected T4 cells, suggesting minimal cytotoxicity. The antiviral effects of these compounds in a micromolar concentration range have been shown to be nonsignificant (<30%) against HIV-1. Three-dimensional parameter focusing of the physicochemical properties (i.e., log P and V _w) and the marginal antiviral activities shows that the marginally active compounds lie in a region different from the inactive compounds. QSAR analysis of the two subsets shows that the cytotoxicity correlates well with the electronic and lipophilic parameters. The results of the QSAR analysis can serve as guidelines for further structural modification of this series of compounds to minimize the cytotoxicity against host cells.     

Synthesis of aryl aldimines and their activity against fungi of clinical interest

Aldimines are aldehyde‐derived compounds that contain a C=N group. Besides its broad industrial applications, this class of non‐naturally occurring compounds are found to possess antibacterial, antifungal, antimalarial, antiproliferative, anti‐inflammatory, antiviral, and antipyretic properties. Based on this, six aryl aldimines were synthesized from the condensation of aromatic amines with benzaldehydes. The antifungal activities of synthesized compounds were evaluated against nineteen fungal strains that included Candida and Aspergillus species, Cryptococcus neoformans. The aryl aldimines 2‐(benzylideneamino)phenol ( 3 ) and 4‐(benzylideneamino)phenol ( 8 ) were the most active compounds against the fungi studied. Compounds 3 and 8 efficiently inhibited the metabolism of C. neoformans mature biofilm.     

Substituted adamantylphthalimides: Synthesis,antiviral and antiproliferative activity

In this study, three groups of adamantylphthalimides, bearing different substituents at the phthalimide moiety, N-(4′-R²)phthalimidoadamantanes ( 1 – 7 ), 3-[N-(4′-R²)phthalimido]-1-adamantanols ( 8 – 10 ), and 3-[N-(4′-R²)phthalimido]adamantane-1-carboxylic acids ( 11 – 15 ), were synthesized and screened against tumor cells and viruses. The most potent compounds are not substituted at the adamantane and bear an OH or NH₂ substituent at the phthalimide (compounds 3 and 5 ). The antiproliferative activities of compounds 3 and 5 are in the micromolar range, much higher than the one of thalidomide. A minor antiviral activity against cytomegalovirus and varicella-zoster virus was found for compounds 3 and 5 , but these compounds lacked selectivity. The results presented are important for the rational design of the next-generation compounds with anticancer and antiviral activities.     

Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides

A series of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazide derivatives (1–12) was tested for their, in vitro antimycobacterial activity against Mycobacterium tuberculosis, and compound 2 was found to be more active than isoniazid. The antiviral screening results indicated that none of the tested compounds was active against a broad variety of DNA and RNA viruses at subtoxic concentrations, except compounds 8 and 10 that proved to be active against DNA viruses at concentrations close to their cytostatic potential. The synthesized compounds were also screened for their antimicrobial potential against S. aureus, B. subtilis, E. coli, C. albicans and A. niger, and the results indicated that compounds having Br, OCH₃ and Cl groups were highly active. The multi-target QSAR models indicated the importance of lipophilic (log P) and topological parameters (³χ^v) in describing the antimicrobial activity.     

Synthesis and antiviral activity of 2-amino-3-ethoxycarbonylpyrazine derivatives

A series of substituted 2-amino-3-ethoxycarbonylpyrazines containing indole, resorcinol, thiophenol, ethyl cyanoacetate, indandione, and antipyrine moieties was obtained via reactions of nucleophilic substitution of hydrogen in the initial 2-aminopyrazine-1-oxides. Some of the synthesized compounds inhibit the reproduction of measles viruses and exhibit a weak antiviral activity with respect to Marburg virus. However, most of the new substituted pyrazines are not cytotoxic and exhibit no activity against ortho-poxviruses and measles viruses. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 12, pp. 12–16, December, 2005.     

Design,Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

相似文献   

Study of the effects on DNA of two novel nucleoside derivatives synthesized as potential anti-HIV agents

The pursuit of antiviral active compounds against different classes of viruses, in particular HIV, HBV, and HTLV is an area of important and intense research. In the current study, two novel nucleoside derivatives belonging to a new class of isoxazolidine were successfully synthesized as potential anti-HIV agents by replacement of the furanose ring by a N,O-heterocyclic ring Both compounds were investigated for biological activity, namely, mutagenic and antimutagenic properties. Using Salmonella typhimurium strains TA97, TA100, and TA102, both compounds proved to be nonmutagenic, which may be considered an encouraging result to further elucidate other biological activities. Antimutagenic testing of the synthesized compounds revealed that they are active against the base-pair substitution mutagen sodium azide. However, they did not show any indication as antimutagenic agents against hydrogen peroxide and mitomycin C (oxidative mutagens) or against nitrophenylenediamine (a base-pair substitution and frameshift mutagen). Structure-activity relationship is also discussed. Testing these compounds as antiviral agents is highly recommended.     

Research progress on antiviral constituents in traditional Chinese medicines and their mechanisms of action

ContextViruses have the characteristics of rapid transmission and high mortality. At present, western medicines still lack an ideal antiviral. As natural products, many traditional Chinese medicines (TCM) have certain inhibitory effects on viruses, which has become the hotspot of medical research in recent years.ObjectiveThe antiviral active ingredients and mechanisms of TCM against viral diseases was studied in combination with the pathogenesis of viral diseases and antiviral effects.Materials and methodsEnglish and Chinese literature from 1999 to 2021 was collected from databases including Web of Science, PubMed, Elsevier, Chinese Pharmacopoeia 2020 (CP), and CNKI (Chinese). Traditional Chinese medicines (TCM), active ingredients, antiviral, mechanism of action, and anti-inflammatory effect were used as the key words.ResultsThe antiviral activity of TCM is clarified to put forward a strategy for discovering active compounds against viruses, and provide reference for screening antivirus drugs from TCM. TCM can not only directly kill viruses and inhibit the proliferation of viruses in cells, but also prevent viruses from infecting cells and causing cytophilia. It can also regulate the human immune system, enhance human immunity, and play an indirect antiviral role.Discussion and conclusionBased on the experimental study and antiviral mechanism of TCM, this paper can provide analytical evidence that supports the effectiveness of TCM in treating virus infections, as well as their mechanisms against viruses. It could be helpful to provide reference for the research and development of innovative TCMs with multiple components, multiple targets and low toxicity.     

Synthesis and biological activity of water-soluble polymer complexes of arbidol

We have synthesized water-soluble complexes between the antiviral drug arbidol and polymer compounds with molecular masses of 19–31 kDa representing copolymers of acrylamide (AA) and 2-acrylamido-2-methylpropanesulfonic acid (AAMPS). The complexes are less toxic than arbidol and retain the high level of antiviral activity of this drug. The content of arbidol in the obtained complexes is within 26.4–32.1 mass%. The antiviral activity of the synthesized polymeric complexes against all studied viruses, including human epidemic influenza virus A (H3N2), bird highly pathogenic influenza virus A (H5N1), herpes type 1 virus (HSV-1), and adenovirus type III (AV-III) is comparable to the antiviral effect of nonmodified arbidol. The in vitro toxicity of the obtained complexes is about one order of magnitude lower than that of nonmodified arbidol; the pharmacological index, four times that of the initial low-molecular-weight drug. The synthesized water-soluble polymer complexes of arbidol can be useful in pharmacology since they can serve as the basis for new effective and safe parent antiviral substances and related formulations.     

Quantitative Structure–Activity Relationships (QSARs) of Pyrimidine Nucleosides as HIV-1 Antiviral Agents

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.     

Potent virucidal effect of pheophorbide a and pyropheophorbide a on enveloped viruses

In this study, we evaluated the inhibitory effect of ethanol and aqueous extracts from a stem of Opuntia ficus indica on replication of three kinds of viruses: two enveloped viruses [herpes simplex virus type 2 (HSV-2), influenza A virus (IFV-A)], and one non-enveloped virus [poliovirus type 1 (PV-1)]. Only ethanol extract from the cactus stem showed significant antiviral activity in vitro. Two chlorophyll derivatives, pheophorbide a and pyropheophorbide a, were isolated as active substances exhibiting potent virucidal effects on HSV-2 and IFV-A, but no activity against PV-1 was observed. These findings suggest that these active compounds might recognize specific glycoproteins of enveloped viruses, precluding their binding to host cell receptors and inhibiting viral infections.     

(Naphthalen-1-yloxy)-acetic acid benzylidene/(1-phenyl-ethylidene)-hydrazide derivatives: synthesis, antimicrobial evaluation, and QSAR studies

A series of (naphthalen-1-yloxy)-acetic acid hydrazides (1–36) was synthesized and screened, in vitro, for antibacterial, antifungal, and antiviral activities. The results of antiviral activity showed that none of the tested compounds was active against viruses at subtoxic concentrations. Further, the antimicrobial screening results demonstrated that compounds having 3,4,5-trimethoxy benzaldehyde (18), o-Br, p-CN (31), and m-NO₂ acetophenone (32) substituents were the most active ones against tested strains. QSAR investigations revealed that multi-target QSAR models were effective in describing the antimicrobial activity.