Acyclovir Drugs Research Articles

Synthesis, antiviral screening, and in silico investigations of new pyrimidine and pyridopyrimidine derivatives: Finding new therapeutic prospects to combat the herpes simplex virus (HSV-1)

In the quest for novel antiviral agents, a new set of fourteen pyrimidine and pyridopyrimidine derivatives (4–11) have been synthesized via different chemical transformations starting from 1,3-indandione 1. These derivatives were characterized by 1H NMR, 13C NMR, FT-IR, and MS. Following the in vitro evaluation of some derivatives of these synthetic compounds against HSV-1, the most promising compounds, 4b and 6, had their mechanisms of action examined. The most potent compounds (4b and 6) were also examined by applying density-functional theory (DFT) to ascertain their molecular structures and geometries. Molecular docking studies for compounds 4b, 5b, and 6 were performed against the Herpes simplex virus type-1 target proteins (PDB ID: 2GIY, 2KI5, and 3FOT) to anticipate the antiviral active sites of the compounds under investigation. Docking results and the compound's strong contact with the target proteins indicated that compounds 4b and 6 had energy scores that were on par with or higher than those of the acyclovir drug. Both in silico and in vitro results are in agreement.

Surface-Enhanced Raman scattering (SERS) filter paper substrates decorated with silver nanoparticles for the detection of molecular vibrations of Acyclovir drug

Acyclovir (ACV) drug, a common antiviral agent, is frequently used as the primary clinical treatment method for treating hepatitis B, herpes simplex, and varicella zoster viruses due to its potent therapeutic effect. In patients with compromised immune systems, this medication can stop cytomegalovirus infections, and high doses of this drug are required; however, such prescription leads to kidney toxicity. Therefore, timely and accurate detection of ACV is crucial in many areas. Surface-Enhanced Raman Scattering (SERS) is a reliable, rapid, and precise approach for the identification of trace biomaterials and chemicals. Filter paper substrates decorated with silver nanoparticles (AgNPs) were applied as SERS biosensors to detect ACV and control its adverse effects. Initially, a chemical reduction procedure was utilized to produce AgNPs. Afterward, UV–Vis, FE-SEM, XRD, TEM, DLS, and AFM were employed to examine the properties of prepared AgNPs. In order to prepare SERS-active filter paper substrates (SERS-FPS) to detect Molecular vibrations of ACV, AgNPs prepared by immersion method were coated on filter paper substrates. Moreover, the UV–Vis DRS analysis was carried out to assess the stability of filter paper substrates and SERS-FPS. The AgNPs reacted with ACV after being coated on SERS-active plasmonic substrates and could sensitively detect ACV in small concentrations. It was discovered that the limit of detection of SERS plasmonic substrates was 10-12 M. Moreover, the mean RSD for ten repeated tests was calculated as 4.19%. The enhancement factor for detecting ACV using the developed biosensors was calculated to be 3.024 × 105 and 3.058 × 105 experimentally and via simulation, respectively. According to the Raman results, SERS-FPS for the detection of ACV, fabricated by the present methods, showed promising results for SERS-based investigations. Furthermore, these substrates showed significant disposablity, reproducibility, and chemical stability. Therefore, the fabricated substrates are capable to be employed as potential SERS biosensors to detect trace substances.

Preparation and Characterization of Poly(vinyl acetate-co-2-hydroxyethyl methacrylate) and In Vitro Application as Contact Lens for Acyclovir Delivery.

A series of poly(vinyl acetate-co-2-hydroxyethylmethacrylate)/acyclovir drug carrier systems (HEMAVAC) containing different acyclovir contents was prepared through bulk free radical polymerization of 2-hydroxyethyl methacrylate with vinyl acetate (VAc) in presence of acyclovir (ACVR) as the drug using a LED lamp in presence of camphorquinone as the photoinitiator. The structure of the drug carrier system was confirmed by FTIR and 1HNMR analysis, and the uniform dispersion of the drug particles in the carrier was proved by DSC and XRD analysis. The study of the physico-chemical properties of the prepared materials, such as the transparency, swelling capacity, wettability and optical refraction, was carried out by UV-visible analysis, a swelling test and measurement of the contact angle and the refractive index, respectively. The elastic modulus and the yield strength of the wet prepared materials were examined by dynamic mechanical analysis. The cytotoxicity of the prepared materials and cell adhesion on these systems were studied by LDH assay and the MTT test, respectively. The results obtained were comparable to those of standard lenses with a transparency of 76.90-89.51%, a swelling capacity of 42.23-81.80% by weight, a wettability of 75.95-89.04°, a refractive index of 1.4301-1.4526 and a modulus of elasticity of 0.67-1.50 MPa, depending on the ACVR content. It was also shown that these materials exhibit no significant cytotoxicity; on the other hand, they show significant cell adhesion. The in vitro dynamic release of ACVR in water revealed that the HEMAVAC drug carrier can consistently deliver uniformly adequate amounts of ACVR (5.04-36 wt%) over a long period (7 days) in two steps. It was also found that the solubility of ACVR obtained from the release process was improved by 1.4 times that obtained by direct solubility of the drug in powder form at the same temperature.

Ultrasensitive electrochemical detection for nanomolarity Acyclovir at ferrous molybdate nanorods and graphene oxide composited glassy carbon electrode

An electrochemical sensor based on ferrous molybdate (FeMoO4) loaded graphene oxide composites was prepared and used for the ultrasensitive detection of Acyclovir in nanomolar concentrations. FeMoO4 nanorods were prepared by hydrothermal method, and loaded with graphene oxide by ultrasonication. The materials were characterized by Scanning Electron Microscopy, X-ray diffractometer and Energy Dispersive Spectroscopy. The electrochemical sensor was fabricated by drop-coating method for the determination of Acyclovir. The sensing performance was investigated by cyclicvoltammetry, electrochemical impedance and linear sweep voltammogram. The results showed that the optimal signals appeared on the electrode. Furthermore, the oxidation peak current was linearly related to the Acyclovir concentration in the range of 0.1–10 μM and 10–100 mM. The limit of detection was 20 nM (S/N = 3). The sensor was used to analyze in process and in situ Acyclovir drug samples with good recoveries of 95.0–100.0% and excellent accuracy in nanomolarity.

Ocular and Facial Herpes Zoster and Meningitis in an Adult after Zoster Vaccination

Purpose: To report a case of ocular and facial herpes zoster and meningitis after herpes zoster vaccination.Case summary: A 60-year-old man was administered Zostavax® on his left arm; he developed a vesicular rash over his left eye and forehead 4 days afterwards. He started antiviral drugs for the rash, and visited the hospital for severe headache and spread of the rash to involve the tip of his nose, face, and palate by day 7. He was taking Synthyroid® (Bukwang Pharmaceuticals, Seoul, Korea) since his thyroidectomy for thyroid cancer 6 years ago. He had never been diagnosed with chickenpox, but had an episode of red facial rash in childhood. Slit-lamp examination revealed conjunctival chemosis, hyperemia, and a pseudodendrite in the peripheral cornea. The anterior chamber was quiet, and there were no significant findings on his brain magnetic resonance imaging. Varicella zoster virus was detected in the cerebrospinal fluid by polymerase chain reaction. The patient was treated with oral acyclovir drugs and topical ganciclovir, levofloxacin, and bromfenac. One week later, the pseudodendrite disappeared and conjunctival chemosis improved. There was no recurrence during 6 months follow-up.Conclusions: Reactivation of ocular or facial herpes zoster or meningitis after zoster vaccination may occur, rarely. Immediate antiviral treatment is required in these cases.

Synthesis, characterization and antibacterial studies of Schiff bases of acyclovir

There is a crucial medical need for the progress of new antibacterial agents with new and more efficient mechanisms. Schiff bases are stated to have a wide range of pharmacological activities, including antimicrobial, antibacterial, antifungal, antioxidant, and anticancer activities, which are largely due to the distinguishing C=N group. Furthermore, heterocyclic compounds containing acyclic hydroxylated side chains, for example, acyclovir (ACV), are an essential class of antiviral acyclonucleosides. Therefore, this work was to synthesize and evaluate a new series of acyclovir analogues bearing a Schiff base moiety. Some of Schiff's bases synthesis in an ethanolic solution of drug, aldehydes, and glacial acetic acid as a catalyst followed in the synthesis of substituted acyclovir drug compounds. In this work, two new series of acyclovir analogues bearing a Schiff base moiety were Synthesised, characterized, and confirmed by various spectral techniques like FTIR, CHN, and 1HNMR spectra, in addition to melting point and retardation factor (Rf.). The biological activity of synthesized Schiff base compounds measured against a panel of various bacteria. The results revealed that these compounds showed antibacterial activity against Gram-positive bacteria such as bacillus and Gram-negative bacteria such as proteus, E-coli, pseudomonas, and klebsiella. It concluded that synthesized Schiff base compounds showed higher antibacterial activity than acyclovir that they derived from it.

Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products

PurposeTo examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments.MethodsThree acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a “reference” formulation (evaluated twice) was compared to the “test” in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers.ResultsSC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that ‘compartment’ to be estimated.ConclusionsAcyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.

INFLUENCE OF FORMULATION PARAMETERS ON DISSOLUTION RATE ENHANCEMENT OF ACYCLOVIR USING LIQUISOLID FORMULATION

Objective: The objective of this research work is to explore the use of liquisolid technique in enhancement of acyclovir dissolution rate. This current study was planned to assess the impact of different formulation variables, such as non-volatile liquid type and concentrations of acyclovir on its dissolution rates profile. Method: Acyclovir liquisolid tablets were prepared with Tween 60 (liquid vehicle), Microcrystalline cellulose PH 102 (acted as a carrier to turn liquid medication into free-flowing powder) and Syloid XDP (coating material). In vitro, drug dissolution rate of liquisolid formulations of acyclovir was performed and compared with pure acyclovir drug using USP dissolution apparatus (Type II) for 60 min at a paddle speed of 50 rpm and filled with 900 mL of distilled water. Results: The dissolution study showed that 94.1% of the drug was released in 60 min of ratio 10 while only 66% of the pure drug acyclovir was released in 60 min. Hence, present work concluded that the acyclovir dissolution rate profile has been improved with the formation of liquisolid formulations. Conclusion: From the present study, it may be ratified that the drug dissolution rate of acyclovir has been improved with the utilization of liquisolid formulations approach.

Identification and Determination of Potential Impurities Present in the Acyclovir Drug Substance by GC-MS

Identification and Determination of Potential Impurities Present in the Acyclovir Drug Substance by GC-MS

Ethyl phosphoramidates of acyclovir: design, synthesis, molecular docking (HN Protein), and evaluation of antiviral and antioxidant activities

Synthesis of a series of new ethyl phosphoramidates 9a–j of acyclovir through phosphorylation of hydroxy group followed by substitution of numerous amines/amino acid esters 7a–j was accomplished. The structures of newly synthesized compounds were elucidated by spectroscopic data such as IR, NMR (1H, 13C, and 31P) and mass spectrophotometery, and elemental analyses. The synthesized products were screened for their antiviral activity against Newcastle disease virus, antioxidant potency by α, α-diphenyl-β-picrylhydrazyl free radical scavenging and nitric oxide radical scavenging methods, and antioxidant capacity by Ferric reducing antioxidant power method. The compound bearing 1-hydroxy 2-butylamine, 9c and amino acid ester derivatives, bonded with leucine methyl ester 9h and tyrosine methyl ester 9j were found to be potent inhibiters of Newcastle disease virus than that of acyclovir drug. The compounds, 9c (IC50 value, 22.5 ± 1.00 μg/mL), 9i (IC50 value, 21.5 ± 1.00 μg/mL) and 9j (IC50 value, 19.0 ± 1.50 μg/mL) were exhibited promising antioxidant activity while other compounds displayed moderate to good antioxidant activity. Docking study using molecular docking environment into haemaglutinin–neuraminidase protein has been carried out to find the potential selectivity and binding orientation of these new compounds into protein binding site. Interestingly, all the title compounds except 9a and 9g docked well into HN protein with considerable binding affinities better than that of acyclovir drug.

Improving oral bioavailability of acyclovir using nanoparticulates of thiolated xyloglucan

Acyclovir a BCS class III drug exhibits poor bioavailability due to limited permeability. The intention of this research work was to formulate and characterize thiolated xyloglucan polysaccharide nanoparticles (TH-NPs) of acyclovir with the purpose of increasing its oral bioavailability. Acyclovir-loaded TH-NPs were prepared using a cross-linking agent. Interactions of formulation excipients were reconnoitered using Fourier transform infrared spectroscopy (FT-IR). The formulated nanoparticles were lyophilised by the addition of a cryoprotectant and characterized for its particle size, morphology and stability and optimized using Box Behnken Design.The optimized TH-NP formulation exhibited particle size of 474.4±2.01 and an entrapment efficiency of 81.57%. A marked enhancement in the mucoadhesion was also observed. In-vivo study in a rat model proved that relative bioavailability of acyclovir TH-NPs is ∼2.575 fold greater than that of the marketed acyclovir drug suspension.

English

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC/MS/MS) method was developed and validated for the trace analysis (>1 ppm level) of p-Toluenesulfonicacid, a genotoxic impurity, in acyclovir drug substances. The chromatographic separation was achieved on Symmetry C-18 (150 X 4.6mm, 3.5μm) column using a mobile phase consisting of 5 mM ammonium acetate and methanol (70:30 v/v) at flow rate of 0.4 mL /min. The API-4000 LC/MS/MS was operated on an electrospray in negative mode. The selected ion monitoring (SIM) mode was used during the analytical run and it is able to quantitate up to 1.5 ppm of p-Toluenesulfonicacid. The newly developed method was validated as per achieved on International Conference on Harmonization (ICH) guidelines

Preparation and characterization of nanoparticles of carboxymethyl cellulose acetate butyrate containing acyclovir

Nanoparticles of carboxymethyl cellulose acetate butyrate complexed with the poorly soluble antiviral drug acyclovir (ACV) were produced by precipitation process and the formulation process and properties of nanoparticles were investigated. Two different particle synthesis methods were explored—a conventional precipitation method and a rapid precipitation in a multi-inlet vortex mixer. The particles were processed by rotavap followed by freeze-drying. Particle diameters as measured by dynamic light scattering were dependent on the synthesis method used. The conventional precipitation method did not show desired particle size distribution, whereas particles prepared by the mixer showed well-defined particle size ~125–450 nm before and after freeze-drying, respectively, with narrow polydispersity indices. Fourier transform infrared spectroscopy showed chemical stability and intactness of entrapped drug in the nanoparticles. Differential scanning calorimetry showed that the drug was in amorphous state in the polymer matrix. ACV drug loading was around 10 wt%. The release studies showed increase in solution concentration of drug from the nanoparticles compared to the as-received crystalline drug.

Utilization of Crosslinked Starch Nanoparticles as a Carrier for Indomethacin and Acyclovir Drugs

An eco-friendly nanoprecipitation technique was put forward to synthesize native starch nanoparticles loaded with insoluble drugs such as indomethacin (IND) and Acyclovir (ACV). Factors studied to find out the optimum conditions for preparation of different formulations of crosslinked starch nanoparticles (TPP-StNPs) loaded with insoluble drugs. The factors are 20 mg, 50 mg of drug concentration and 0.5, 1 g of sodium tripolyphosphate (STPP) while the concentration of starch and surfactant were kept constant. World-class facilities as particle size analyzer, poly dispersity index (PDI), zeta potential, TEM, XRD, FT-IR, UV-vis spectroscopy and DSc were used for evaluation of the resultant crosslinked starch nanoparticles loaded with drug. The sustained release of drugs were evaluated using entrapment efficiency and in vitro release. The data obtained confirmed that there is no chemical interaction between drug (IND, ACV) and crosslinked starch nanoparticles. The results indicate that the best formula for IND loaded starch nanoparticles was 0.5 g STPP and 20 mg IND while the best formula for ACV nanoparticles was at 0.5 g STPP and 50 mg ACV drug.

Mechanisms Associated with HIV-1 Resistance to Acyclovir by the V75I Mutation in Reverse Transcriptase

It has recently been demonstrated that the anti-herpetic drug acyclovir (ACV) also displays antiviral activity against the human immunodeficiency virus type 1 (HIV-1). The triphosphate form of ACV is accepted by HIV-1 reverse transcriptase (RT), and subsequent incorporation leads to classical chain termination. Like all approved nucleoside analogue RT inhibitors (NRTIs), the selective pressure of ACV is associated with the emergence of resistance. The V75I mutation in HIV-1 RT appears to be dominant in this regard. By itself, this mutation is usually not associated with resistance to currently approved NRTIs. Here we studied the underlying biochemical mechanism. We demonstrate that V75I is also selected under the selective pressure of a monophosphorylated prodrug that was designed to bypass the bottleneck in drug activation to the triphosphate form (ACV-TP). Pre-steady-state kinetics reveal that V75I discriminates against the inhibitor at the level of catalysis, whereas binding of the inhibitor remains largely unaffected. The incorporated ACV-monophosphate (ACV-MP) is vulnerable to excision in the presence of the pyrophosphate donor ATP. V75I compromises binding of the next nucleotide that can otherwise provide a certain degree of protection from excision. Collectively, the results of this study suggest that ACV is sensitive to two different resistance pathways, which warrants further investigation regarding the detailed resistance profile of ACV. Such studies will be crucial in assessing the potential clinical utility of ACV and its derivatives in combination with established NRTIs.

Poly(ethylene- co-vinyl acetate) copolymer matrix for delivery of chlorhexidine and acyclovir drugs for use in the oral environment: Effect of drug combination, copolymer composition and coating on the drug release rate

Objectives This study utilizes a bio-compatible ethylene vinyl acetate (EVA) copolymer to deliver drugs at therapeutic levels over extended periods of time. The release rate of an anti-fungal and an anti-microbial drug namely acyclovir (ACY) and chlorhexidine diacetate (CDA) from EVA was investigated individually and as a mixture. The effect of drug combination, the composition of the copolymer and the coating of the matrix with a different polymer on the rate of drug release are presented. Method Polymer casting solutions were prepared by homogeneously dissolving EVA copolymer and the drugs in the ratio (40:1) in dichloromethane. The drugs ACY and CDA were used individually as well as in three different weight ratios maintaining the total drug concentration in the polymer at 2.5%. Different concentrations of vinyl acetate (VA) 28, 32 and 40% in the EVA matrix were used to study the release of either ACY or CDA alone while 40% VA was used for the release study of the individual drug as well as their mixtures. Thin square films of 3 cm × 3 cm with a thickness of 0.7 mm were cut from the dry sheet obtained by solvent evaporation. Coated films were prepared by dipping ACY and CDA drug-loaded EVA films (VA 40%) into EVA copolymer of VA 32% and then dried. All of the drug-loaded samples were extracted at 37 °C in 10 ml distilled water that was replaced daily. The rate of individual drug release was measured by UV-spectrophotometer while the mixtures of drugs were measured by high performance liquid chromatography (HPLC). Results The release rate of ACY is higher than that of CDA both individually and in the ACY/CDA 50/50 mixture. In the other mixtures, the release of the drug is proportional to its concentration in the mixture. Total release of ACY is higher than CDA in most compositions. The effect of increasing the vinyl acetate content of the EVA matrix increased the drug release rate ( p = 0.02) while coating of films resulted in a decrease of the release rate of the drugs. Significance Measurements of the in vitro rate of drug release showed that there was a sustained release of drug at an almost constant concentration over extended period of time, thus providing a basis for oral treatment modality. We show that it is possible to alter the rate of drug release in the EVA matrix to a desired value by: (1) changing the composition of the EVA copolymer, (2) altering the mixtures of drugs and (3) coating the matrix with additional polymer. The use of mixtures of drugs that can enhance or decrease the rate of drug release may prove more effective in treating persistent oral infections in immunocompromised patients.