Effect of N'-Benzyl Substituted Uracil and the Analogues on HIV-1 Inhibition

2021 ◽  
pp. 2723-2728
Author(s):  
Olga Nesterova ◽  
Dmitrii Babaskin ◽  
Yuliya Tikhonova ◽  
Natalia Molodozhnikova ◽  
Sergey Kondrashev
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Uracil Derivatives ◽  
Half Maximal Effective Concentration ◽  
Infected Cells ◽  
New Generation ◽  
Anti Hiv ◽  
Hiv 1

The aim of the research is to study the effect of the synthesis of uracil derivatives on the HIV-1 activity. To achieve the goal, the following tasks were determined: to study the specificity of possible compounds for HIV-1 treatment; to synthesize uracil derivatives; to study the effect of the compounds on HIV-1 replication in vitro and select the most optimal concentrations, considering the cytotoxic effect; to determine the most effective anti-HIV-1 compounds for further research. Thus, nine new uracil analogues have been synthesized and proved to be inhibitors of HIV-1. Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl) uracil by other functional groups or N (1)-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.081 and 0.069μM) and selective (selectivity index =679 and 658), respectively. Structure-activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase. Two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) were discovered as novel anti-HIV agents. Compound’s activity against HIV-1 was determined based on inhibition of virus-induced cytopathogenicity in MT-4 cells. The compounds were tested for efficacy in infected cells and cytotoxicity. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains. Thus, it will contribute to the development of a new generation of compounds effective against different viruses, considering their quickly mutation and increased resistance.

scholarly journals Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)Uracil Derivatives with Potential Anti-HIV Activity

2011 ◽  
Vol 22 (2) ◽  
pp. 57-65 ◽  
Author(s):  
Yohei Isono ◽  
Norikazu Sakakibara ◽  
Paula Ordonez ◽  
Takayuki Hamasaki ◽  
Masanori Baba ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Structural Modifications ◽  
Half Maximal Effective Concentration ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv Agents ◽  
Substituted 1 ◽  
Anti Hiv ◽  
Hiv 1

Background: Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1. Methods: Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N1-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. Results: These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.067 and 0.069 μM) and selective (selectivity index =685 and 661), respectively. Structure–activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase. Conclusions: We discovered two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) as novel anti-HIV agents. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains.

scholarly journals 4′-C-Methyl-2′-Deoxyadenosine and 4′-C-Ethyl-2′-Deoxyadenosine Inhibit HIV-1 Replication

2011 ◽  
Vol 55 (5) ◽  
pp. 2379-2389 ◽  
Author(s):  
B. Christie Vu ◽  
Paul L. Boyer ◽  
Maqbool A. Siddiqui ◽  
Victor E. Marquez ◽  
Stephen H. Hughes
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Cultured Cells ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Viral Dna ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTIt is important to develop new anti-HIV drugs that are effective against the existing drug-resistant mutants. Because the excision mechanism is an important pathway for resistance to nucleoside analogs, we are preparing analogs that retain a 3′-OH and can be extended after they are incorporated by the viral reverse transcriptase. We show that 4′-C-alkyl-deoxyadenosine (4′-C-alkyl-dA) compounds can be phosphorylated in cultured cells and can inhibit the replication of HIV-1 vectors: 4′-C-methyl- and 4′-C-ethyl-dA show both efficacy and selectivity against HIV-1. The compounds are also effective against viruses that replicate using reverse transcriptases (RTs) that carry nucleoside reverse transcriptase inhibitor resistance mutations, with the exception of the M184V mutant. Analysis of viral DNA synthesis in infected cells showed that viral DNA synthesis is blocked by the incorporation of either 4′-C-methyl- or 4′-C-ethyl-2′-deoxyadenosine.In vitroexperiments with purified HIV-1 RT showed that 4′-C-methyl-2′-dATP can compete with dATP and that incorporation of the analog causes pausing in DNA synthesis. The 4′-C-ethyl compound also competes with dATP and shows a differential ability to block DNA synthesis on RNA and DNA templates. Experiments that measure the ability of the compounds to block DNA synthesis in infected cells suggest that this differential block to DNA synthesis also occurs in infected cells.

Synthesis and anti-HIV-1 Activity of [1-[2′,5′-Bis-O-(Tert-Butyldimethylsilyl)-β-L-Ribofuranosyl]Thymine]-3′-Spiro-5″-(4″-Amino-1″,2″-Oxathiole-2″,2″-Dioxide) (L-TSAO-T), the L-enantiomer of the Highly Specific HIV-1 Reverse Transcriptase Inhibitor TSAO-T

1995 ◽  
Vol 6 (6) ◽  
pp. 365-370 ◽  
Author(s):  
S. T. Ingate ◽  
M.-J. Camarasa ◽  
E. De Clercq ◽  
J. Balzarini
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Antiretroviral Activity

The L-isomer of the potent HIV-1-RT inhibitor TSAO-T has been stereospecifically synthesized and tested for its ‘ in vitro’ antiretroviral activity against HIV-1. Unlike the D-isomer, the L-isomer did not show appreciable inhibition of HIV-1 replication. The cytotoxicity was comparable with the cytotoxicity of the D-enantiomer.

scholarly journals Anti-HIV-1 Activity of Calanolides Used in Combination with other Mechanistically Diverse Inhibitors of HIV-1 Replication

2000 ◽  
Vol 11 (5) ◽  
pp. 321-327 ◽  
Author(s):  
Robert W Buckheit ◽  
Julie D Russell ◽  
Ze-Qi Xu ◽  
Michael Flavin
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Drug Combinations ◽  
Wild Type Virus ◽  
Combination Drug ◽  
Challenge Virus ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Calanolide A

The natural product (+)-calanolide A, a unique non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 replication, is currently being evaluated in clinical trials in the USA. (+)-Calanolide A, the congeners costatolide and dihydrocostatolide, and (+)-12-oxo(+)-calanolide A, were evaluated in combination with a variety of mechanically diverse inhibitors of HIV replication to define the efficacy and cellular toxicity of potential clinical drug combinations. These assays should be useful in prioritizing the use of different combination drug strategies in a clinical setting. The calanolides exhibited synergistic antiviral interactions with other nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Additive interactions were also observed when the calanolides were used with representative compounds from each of these classes of inhibitors. No evidence of either combination toxicity or antagonistic antiviral activity was detected with any of the tested compounds. The combination antiviral efficacy of three-drug combinations involving the calanolides, and the efficacy of two- and three-drug combinations using a (+)-calanolide A-resistant challenge virus (bearing the T139I amino acid change in the reverse transcriptase), was also evaluated in vitro. These assays suggest that the best combination of agents based on in vitro anti-HIV assay results would include the calanolides in combination with lamivudine and nelfinavir, since this was the only three-drug combination exhibiting a significant level of synergy. Combination assays with the (+)-calanolide A-resistant strain yielded identical results as seen with the wild-type virus, although the concentration of the calanolides had to be increased.

scholarly journals In Vivo Toxicity, Pharmacokinetics, and Anti-Human Immunodeficiency Virus Activity of Stavudine-5′-(p-Bromophenyl Methoxyalaninyl Phosphate) (Stampidine) in Mice

2002 ◽  
Vol 46 (11) ◽  
pp. 3428-3436 ◽  
Author(s):  
Fatih M. Uckun ◽  
Sanjive Qazi ◽  
Sharon Pendergrass ◽  
Elizabeth Lisowski ◽  
Barbara Waurzyniak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Peripheral Blood ◽  
Pharmacokinetic Profile ◽  
Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Dose Levels ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We have evaluated the clinical potential of stavudine-5′-(p-bromophenyl methoxyalaninyl phosphate(stampidine [STAMP]), a novel aryl phosphate derivative of stavudine, as a new anti-human immunodeficiency virus (anti-HIV) agent, by examining its acute, subacute, and chronic toxicity profile in mice as well as by testing its antiviral activity in a surrogate human peripheral blood lymphocyte (Hu-PBL)-SCID mouse model of human AIDS. STAMP was very well tolerated in BALB/c and CD-1 mice, without any detectable acute or subacute toxicity at single intraperitoneal or oral bolus doses as high as 500 mg/kg of body weight. Notably, daily administration of STAMP intraperitoneally or orally for up to 8 consecutive weeks was not associated with any detectable toxicity at cumulative dose levels as high as 6.4 g/kg. Micromolar concentrations of the active STAMP metabolite in plasma were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of a nontoxic 100-mg/kg bolus dose of STAMP. In accordance with its favorable pharmacokinetic profile and in vitro potency, STAMP exhibited dose-dependent and potent in vivo anti-HIV activity in Hu-PBL-SCID mice against a genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor (NRTI)-resistant clinical HIV type 1 (HIV-1) isolate (BR/92/019; D67N, L214F, T215D, K219Q) at nontoxic dose levels. The remarkable in vivo safety and potency of STAMP warrants the further development of this promising new antiretroviral agent for possible clinical use in patients harboring NRTI-resistant HIV-1.

Development of Human Immunodeficiency Virus Type 1Starting with Wild-Type or Nucleoside Reverse Transcriptase Inhibitor Resistant-Strains

2021 ◽  
Author(s):  
Maria E. Cilento ◽  
Aaron B. Reeve ◽  
Eleftherios Michailidis ◽  
Tatiana V. Ilina ◽  
Eva Nagy ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Rnase H ◽  
Phase Iii ◽  
Wild Type ◽  
Resistance Mutations ◽  
Primary Determinant ◽  
Hiv 1

4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA, MK-8591, islatravir) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with exceptional potency against WT and drug-resistant HIV-1, in Phase III clinical trials. EFdA resistance is not well characterized. To study EFdA-resistance patterns as it may emerge in naïve or tenofovir- (TFV), emtricitabine/lamivudine- (FTC/3TC), or zidovudine- (AZT) treated patients we performed viral passaging experiments starting with wild-type, K65R, M184V, or D67N/K70R/T215F/K219Q HIV-1. Regardless the starting viral sequence, all selected EFdA-resistant variants included the M184V RT mutation. Using recombinant viruses, we validated the role for M184V as the primary determinant of EFdA resistance; none of the observed connection subdomain (R358K and E399K) or RNase H domain (A502V) mutations significantly contributed to EFdA resistance. A novel EFdA resistance mutational pattern that included A114S was identified in the background of M184V. A114S/M184V exhibited higher EFdA resistance (∼24-fold) than M184V (∼8-fold) or A114S alone (∼2-fold). Remarkably, A114S/M184V and A114S/M184V/A502V resistance mutations were up to 50-fold more sensitive to tenofovir than WT HIV-1. These mutants also had significantly lower specific infectivity than WT. Biochemical experiments confirmed decreases in the enzymatic efficiency (k cat /K m ) of WT vs. A114S (2.1-fold) and A114S/M184V/A502V (6.5-fold) RTs, with no effect of A502V on enzymatic efficiency or specific infectivity. The rather modest EFdA resistance of M184V or A114S/M184V (8- and 24-fold), their hypersusceptibility to tenofovir, and strong published in vitro and in vivo data, suggest that EFdA is an excellent therapeutic candidate for naïve, AZT-, FTC/3TC, and especially tenofovir-treated patients.

scholarly journals In Vitro and In Silico Antioxidant, Anti-Diabetic, Anti-HIV and Anti-Alzheimer Activity of Endophytic Fungi, Cladosporium uredinicola Phytochemicals

2019 ◽  
Vol 13 ◽  
pp. 13-34
Author(s):  
Melappa Govindappa ◽  
V. Thanuja ◽  
S. Tejashree ◽  
C.A. Soukhya ◽  
Suresh Barge ◽  
...  
Keyword(s):  
Qualitative Method ◽  
Cholinesterase Activity ◽  
Methanol Extract ◽  
High Binding Energy ◽  
Acetyl Cholinesterase ◽  
Gp 120 ◽  
Anti Hiv ◽  
Hiv 1

The present work was aimed to identify phytochemicals in C. uredinicola methanol extract from qualitative, TLC and GC-MS method and evaluated for antioxidant, anti-HIV, anti-diabetes, anti-cholinesterase activity in vitro and in silico. The C. uredinicola extract showed flavonoids, tannins, alkaloids, glycosides, phenols, terpenoids, and coumarins presence in qualitative method. From GC-MS analysis, identified seven different phytochemicals and out of seven, four (coumarin, coumarilic acid, hymecromone, alloisoimperatorin) are coumarins. The C. uredinicola extract have shown significant antioxidant activity in DPPH (73) and FRAP (1359) method. The HIV-1 RT (83.81+2.14), gp 120 (80.24+2.31), integrase (79.43+3.14) and protease (77.63+2.14), DPPIV, β-glucosidase and acetyl cholinesterase activity was significantly reduced by the extract. The 2-diphenylmethyleneamino methyl ester had shown significant interaction with oxidant and HIV-1 proteins whereas alloisoimperatorin have interacted with diabetes and cholinesterase proteins followed by hymecromone with high binding energy. These three phytochemicals are non-carcinogens, non-toxic, readily degradable and have drug likeliness properties. The C. uredinicola phytochemicals are responsible for management of diabetes, HIV-1 and Alzheimer. Further in vivo work is needed to justify our research.

Sign in / Sign up

Export Citation Format

Share Document