Synthesis and Biological Evaluation of Amino Acid Based Mutual Amide Prodrugs of Phenytoin as Anticonvulsant Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Sampada Jangam ◽  
Meenakshi Deodhar ◽  
Sagar Wankhede
Keyword(s):  
Amino Acid ◽  
Anticonvulsant Activity ◽  
Water Solubility ◽  
Biological Evaluation ◽  
Proton Nuclear Magnetic Resonance ◽  
Log P ◽  
Maximal Electroshock ◽  
Sprague Dawley ◽  
Anticonvulsant Agents

Background: Phenytoin (5,5-diphenyl hydantoin) has poor water solubility which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection. Objective: The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine. Methods: These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1 H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (µ), refractive index (n), specific refraction (RS) and molar refraction (RM). Results: The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was performed by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minute at 220 nm. Conclusion: The results obtained from the present work showed that amino acid based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.

Synthesis and biological evaluation of 4-aminoantipyrine analogues

2020 ◽  
Vol 16 ◽  
Author(s):  
Houwei Ren ◽  
Premnath Dhanaraj ◽  
Israel V M V Enoch ◽  
Mosae Selvakumar Paulraj ◽  
Indiraleka M
Keyword(s):  
Cervical Cancer ◽  
Dna Cleavage ◽  
Anticonvulsant Activity ◽  
Biological Activities ◽  
Biological Evaluation ◽  
In Vitro Cytotoxicity ◽  
Dilution Method ◽  
Maximal Electroshock ◽  
Protein Receptors

Objectives: The aim of the present study is to carry out a simple synthesis of aminoantipyrine analogues and exploration of their antibacterial, cytotoxic, and anticonvulsant potential. Methods: The compounds were characterized employing multi-spectroscopic methods. The in vitro pharmacological response of a series of bacteria were screened employing serial dilution method. The derivatives were screened against maximal electro-shock for their anticonvulsant activity. Molecular docking was carried out to optimize the interaction of the compounds with HPV16-E7 receptors. Further, the in vitro cytotoxicity was tested against human cervical cancer (SiHa) cell lines. Results: The compounds show protection against maximal electroshock, esp. 3-nirto- and 4-methyl-3-nitrobenzamido derivatives. In addition, they reveal appreciable DNA cleavage activities and interactions with HPV16-E7 protein receptors, esp. 3,5-dinitro- and 4-methyl-3-nitrobenzamido derivatives. Furthermore, they show potent activity against cervical cancer cells (LD50 value up to 1200 in the case of 4-methyl-3-nitrobenzamido derivative and an inhibition of a maximum of 97% of cells). Conclusions: The simply synthesized aminoantipyrine derivatives show a variety of biological activities like antibacterial and anticancer effects. In addition, this is the first study demonstrating that 4-aminoantipyrine derivatives shows an anticonvulsant activity.

scholarly journals Silver Nanocolloids Loaded with Betulinic Acid with Enhanced Antitumor Potential: Physicochemical Characterization and In Vitro Evaluation

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 152
Author(s):  
Iulia Pinzaru ◽  
Cristian Sarau ◽  
Dorina Coricovac ◽  
Iasmina Marcovici ◽  
Crinela Utescu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Betulinic Acid ◽  
Water Solubility ◽  
Physicochemical Characterization ◽  
A549 Cells ◽  
Drug Carriers ◽  
Biological Evaluation ◽  
Correlation Spectroscopy ◽  
Hydrodynamic Diameter

Betulinic acid (BA), a natural compound with various health benefits including selective antitumor activity, has a limited applicability in vivo due to its poor water solubility and bioavailability. Thus, this study focused on obtaining a BA nano-sized formulation with improved solubility and enhanced antitumor activity using silver nanocolloids (SilCo and PEG_SilCo) as drug carriers. The synthesis was performed using a chemical method and the physicochemical characterization was achieved applying UV-Vis absorption, transmission electron microscopy (TEM), Raman and photon correlation spectroscopy (PCS). The biological evaluation was conducted on two in vitro experimental models—hepatocellular carcinoma (HepG2) and lung cancer (A549) cell lines. The physicochemical characterization showed the following results: an average hydrodynamic diameter of 32 nm for SilCo_BA and 71 nm for PEG_SilCo_BA, a spherical shape, and a loading capacity of 54.1% for SilCo_BA and 61.9% for PEG_SilCo_BA, respectively. The in vitro assessment revealed a cell type- and time-dependent cytotoxic effect characterized by a decrease in cell viability as follows: (i) SilCo_BA (66.44%) < PEG_SilCo_BA (72.05%) < BA_DMSO (75.30%) in HepG2 cells, and (ii) SilCo_BA (75.28%) < PEG_SilCo_BA (86.80%) < BA_DMSO (87.99%) in A549 cells. The novel silver nanocolloids loaded with BA induced an augmented anticancer effect as compared to BA alone.

scholarly journals A N-propionylsulfonamide prodrug of K-5a2 provided improved aqueous solubility and hERG inhibition

2020 ◽  
Author(s):  
Xiaofang Zuo ◽  
Zhipeng Huo ◽  
Dongwei Kang ◽  
Tong Zhao ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Water Solubility ◽  
Parent Drug ◽  
Aqueous Solubility ◽  
Drug Candidate ◽  
Log P ◽  
Vitro Assay ◽  
Subacute Toxicity ◽  
Anti Hiv ◽  
Hiv 1

Abstract Background Having the potential disadvantages and safety risk of the use of anti-HIV-1 drug candidate K-5a2 in the longterm treatment of HIV patients in mind, we set out with the goal of finding a second-generation backup compound of K-5a2 with the appropriate anti-HIV potency, significantly reduced hERG activity, decreased induction of the CYP enzyme, and improved aqueous solubility. Herein, using a N-propionylsulfonamide prodrug strategy, we report the discovery of compound HM-1Methods In vitro assay of anti-HIV activities in TZM-bl and MT-4 cells, metabolic stability in HLM and human plasma, measurements of water solubility and Log P, assay procedures for hERG activity, acute and subacute toxicity experiment and cytochrome P450 inhibition assay were carried out for HM-1.Results HM-1 can be rapidly hydrolyzed to parent drug K-5a2 and exhibited high potency against HIV-1NL4 − 3 strain (EC50 = 7.99 nM) in TZM-bl cells, HIV-1IIIB strain (EC50 = 2.9 nM) and HIV-1Y181C strain (EC50 = 5.5 nM) in MT-4 cells. And it also showed a > 70-fold improvement in aqueous solubility and presented a low acute toxicity in mice (LD50 > 2 g•kg− 1); no obvious organ damage was detected in the assessment of subacute toxicity. Meanwhile, HM-1 also showed 50 times lower hERG inhibition (IC50 = 6.39 µM) than K-5a2 (IC50 = 0.13 µM).Conclusions It was HM-1 appeared to be free of most of the drawbacks associated with K-5a2 and has been selected for further development as an oral anti-HIV-infection agent.

scholarly journals Comparative Evaluation of the Cytotoxicity of Glyphosate-Based Herbicides and Glycine in L929 and Caco2 Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Francesca Truzzi ◽  
Daniele Mandrioli ◽  
Federica Gnudi ◽  
Paul T. J. Scheepers ◽  
Ellen K. Silbergeld ◽  
...  
Keyword(s):  
Amino Acid ◽  
Trypan Blue ◽  
Intestinal Microbiome ◽  
Sprague Dawley ◽  
Literature Report ◽  
Cytotoxic Effects ◽  
Caco2 Cells ◽  
Ic50 Value

Introduction: Glyphosate, an amino acid analog of glycine, is the most widely applied organophosphate pesticide worldwide and it is an active ingredient of all glyphosate-based herbicides (GBHs), including the formulation “Roundup. ” While glycine is an essential amino acid generally recognized safe, both epidemiological and toxicological in vivo and in vitro studies available in literature report conflicting findings on the toxicity of GBHs. In our earlier in vivo studies in Sprague–Dawley rats we observed that exposure to GBHs at doses of glyphosate of 1.75 mg/kg bw/day, induced different toxic effects relating to sexual development, endocrine system, and the alteration of the intestinal microbiome. In the present work, we aimed to comparatively test in in vitro models the cytotoxicity of glycine and GBHs.Methods: We tested the cytotoxic effects of glycine, glyphosate, and its formulation Roundup Bioflow at different doses using MTT and Trypan Blue assays in human Caco2 and murine L929 cell lines.Results: Statistically significant dose-related cytotoxic effects were observed in MTT and Trypan Blue assays in murine (L929) and human (Caco2) cells treated with glyphosate or Roundup Bioflow. No cytotoxic effects were observed for glycine. In L929, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in both MTT and Trypan Blue assays. In Caco2, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in the MTT assays, while a comparable IC50 was observed for glyphosate and Roundup Bioflow in Trypan Blue assays. IC50 for glycine could not be estimated because of the lack of cytotoxic effects of the substance.Conclusion: Glyphosate and its formulation Roundup Bioflow, but not glycine, caused dose-related cytotoxic effects in in vitro human and murine models (Caco2 and L929). Our results showed that glycine and its analog glyphosate presented different cytotoxicity profiles. Glyphosate and Roundup Bioflow demonstrate cytotoxicity similar to other organophosphate pesticides (malathion, diazinon, and chlorpyriphos).

Synthesis and Evaluation of N-substituted (Z)-5-(Benzo[d][1,3]dioxol-5- ylmethylene)-2-Thioxothiazolidin-4-one Derivatives and 5-Substituted- Thioxothiazolidindione Derivatives as Potent Anticonvulsant Agents

2020 ◽  
Vol 18 (10) ◽  
pp. 798-807
Author(s):  
Shiyang Dong ◽  
Yanhua Liu ◽  
Jun Xu ◽  
Yue Hu ◽  
Limin Huang ◽  
...  
Keyword(s):  
Anticonvulsant Activity ◽  
Structural Modification ◽  
Docking Study ◽  
Maximal Electroshock ◽  
Molecular Docking Study ◽  
Rotarod Test ◽  
Protective Index ◽  
Channel Inhibition ◽  
Anticonvulsant Activities

Background: Epilepsy is a serious and common neurological disorder threatening the health of humans. Despite enormous progress in epileptic research, the anti-epileptic drugs present many limitations. These limitations prompted the development of more safer and effective AEDs. Methods: series of N-substituted (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)- 2-thioxothiazolidin-4- one derivatives and 5-substituted-thioxothiazolidindione derivatives were designed, synthesized and tested for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ). Neurotoxicity was determined by the rotarod test. Results: Among them, the most potent 4e displayed high protection against MES-induced seizures with an ED50 value of 9.7 mg/kg and TD50 value of 263.3 mg/kg, which provided 4e with a high protective index (TD50/ED50) of 27.1 comparable to reference antiepileptic drugs. 4e clearly inhibits the NaV1.1 channel in vitro. The molecular docking study was conducted to exploit the results. Conclusion: Stiripentol is a good lead compound for further structural modification. Compound 4e was synthesized, which displayed remarkable anticonvulsant activities, and the NaV1.1 channel inhibition was involved in the mechanism of action of 4e.

Synthesis and Antimicrobial Evaluation of Amino Acid Naphthoquinone Derivatives as Potential Antibacterial Agents

Chemotherapy ◽  
2021 ◽  
Author(s):  
Lluvia Itzel López-López ◽  
Ernesto Rivera-Ávalos ◽  
Cecilia Villarreal-Reyes ◽  
Fidel Martínez-Gutiérrez ◽  
Denisse de Loera
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Amino Acid ◽  
Antimicrobial Activities ◽  
Biological Evaluation ◽  
Culture Collection ◽  
Anticancer Activities ◽  
Broth Microdilution Method

Background: The synthesis and biological evaluation of 1,4-naphthoquinone derivatives are of great interest since these compounds exhibit strong antibacterial, antifungal, antimalarial, and anticancer activities. The electronic properties of naphthoquinones are usually modulated by attaching functional groups containing nitrogen, oxygen and sulfur atoms, which tune their biological potency and selectivity. Methods: A series of 13 amino acid 1,4-naphthoquinone derivatives were synthesized under assisted microwave and ultrasound conditions. The antibacterial activity compounds was tested against American type Culture Collection (ATCC): Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis, as well two multidrug resistant pathogens: Escherichia coli and Staphylococcus aureus from clinical isolated. Minimal inhibitory concentration (MIC) was determined using the broth microdilution method. Results: MIC of derivatives 4–11, 14 and 16 showed antimicrobial activity against gram-positive and gram-negative bacteria. Antimicrobial activities of the compounds 4–8 and 14 were ≤MIC 24.7 μg∙mL-1 against all the reference strain, even more the compound 6 showed the most potent activity with a MIC of 3.9 μg∙mL-1 on S. aureus. On the clinical isolated the compounds 7, 8 and 14 showed a MIC of 49.7 and 24.7 μg∙mL-1 against S. aureus y E. coli respectively. About ADME properties and Osiris analysis, the compounds 4-16 presented high gastrointestinal absorption and good characteristics for oral bioavailability and the compound 14 was the less toxic. Conclusion: amino acid 1,4-naphthoquinone derivatives showed good in vitro antibacterial activity against clinical strains, and modifications on C-3 with cloride atom enhanced the efficiency against same pathogens.

In Methanolic Solvent Synthesis of New MnII, CoII, NiII and CuII Schiff Base of Aromatic β Amino Acids: Spectroscopic, Thermal, Molecular Docking and Antimicrobial Studies

2020 ◽  
Vol 12 (8) ◽  
pp. 1137-1148 ◽  
Author(s):  
Asma S. Al-Wasidi ◽  
Nawal M. Al-Jafshar ◽  
Amal M. Al-Anazi ◽  
Moamen S. Refat ◽  
Nashwa M. El-Metwaly ◽  
...  
Keyword(s):  
Schiff Base ◽  
Molecular Docking ◽  
Amino Acid ◽  
Benzoic Acid ◽  
Molar Conductance ◽  
Schiff Base Complexes ◽  
Proton Nuclear Magnetic Resonance ◽  
Antimicrobial Studies ◽  
Amino Benzoic Acid

In this article, four new Schiff base complexes of Mn(II), Co(II), Ni(II) and Cu(II) complexes have been synthesized with two different compositions as [M(L)2Cl2] · nH2O and [M(L)2(H2O)2]Cl2 · nH2O [where L1 = benzoin-o-amino benzoic acid (aromatic β amino acid) and L2 = benzoin bromo-o-amino benzoic acid (aromatic β amino acid); M = MnII, CoII, NiII and CuII; n = 1, 2 and 4]. These Schiff base complexes were discussed by many tool of analyses like elemental analysis, magnetic susceptibility, molar conductance, mass spectra, infrared spectra "IR," proton nuclear magnetic resonance "1H-NMR," electronic spectral and thermogravimetric analysis (TG/DTG). These complexes have an electrolytic nature within range of 78–174 Ω1 cm–1 mol –1 based on conductance measurements. Magnetic moment and electronic spectral results deduced that the geometry of Mn2+, Co2+ and Ni2+ and Cu2+ complexes has an octahedral configuration. The number of coordinated and uncoordinated water molecules for the synthesized complexes were calculated based on the thermal analysis technique. The kinetic thermodynamic data were estimated by using commonly integral equations of Horowitz-Metzger (HM) and Coats-Redfern (CR). In vitro the antimicrobial activity of both free L1 and L2 ligands in comparable with their metal complexes were evaluated. This study was strengthen by molecular docking against three protein receptors, which attributing to selected organisms already used in vitro study.

scholarly journals Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats

2002 ◽  
Vol 46 (5) ◽  
pp. 1357-1363 ◽  
Author(s):  
Heng Song ◽  
George W. Griesgraber ◽  
Carston R. Wagner ◽  
Cheryl L. Zimmerman
Keyword(s):  
Amino Acid ◽  
High Performance ◽  
Volume Of Distribution ◽  
Water Soluble ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley ◽  
Binding Studies ◽  
Total Body

ABSTRACT In vitro studies have demonstrated that water-soluble, nontoxic phosphoramidates of azidothymidine (zidovudine [AZT]) have significant and specific anti-human immunodeficiency virus and anticancer activity. Although polar, these compounds are internalized and processed to the corresponding nucleoside monophosphates. Eight methyl amide and methyl ester phosphoramidate monoesters composed of d- or l-phenylalanine or tryptophan and AZT were synthesized. The plasma stability and protein binding studies were carried out in vitro. Then in vivo pharmacokinetic evaluations of six of the compounds were conducted. Sprague-Dawley rats received each compound by intravenous bolus dose, and serial blood and urine samples were collected. AZT and phosphoramidate concentrations in plasma and urine were quantitated by high-performance liquid chromatography with UV or fluorescence detection. Pharmacokinetic parameters were calculated by standard noncompartmental means. The plasma half-lives of the phosphoramidates were 10- to 20-fold longer than the half-life of AZT. Although the renal clearances of the phosphoramidates were similar to AZT, their total body clearances were significantly greater than that of AZT. The 3- to 15-fold-larger volume of distribution (V ss) for the phosphoramidates relative to AZT appeared to be dependent on the stereochemistry of the amino acid, with the largest values being associated with the l-amino acids. The increased V ss indicates a much greater tissue distribution of the phosphoramidate prodrugs than of AZT. Amino acid phosphoramidate monoesters of AZT have improved pharmacokinetic properties over AZT and significant potential as in vivo pronucleotides.

Synthesis and Anticonvulsant Activity of α-Amino Acid Amide Derivatives

2019 ◽  
Vol 15 (5) ◽  
pp. 547-561
Author(s):  
Valerie Currier ◽  
Maryam Molki ◽  
Katelyn Fryman ◽  
Lacey D. Rodgers ◽  
A. Michael Crider
Keyword(s):  
Amino Acid ◽  
Side Effects ◽  
Anticonvulsant Activity ◽  
Acid Amide ◽  
New Drugs ◽  
Seizure Threshold ◽  
Maximal Electroshock ◽  
Maximal Electroshock Seizure ◽  
Maximal Electroshock Seizure Test ◽  
Amide Derivatives

Background: Epilepsy is a disease of the central nervous system that affects approximately 50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years, almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action and minimal side effects. Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard battery of anticonvulsant tests. Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α- carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower seizure threshold when evaluated in the intravenous metrazol seizure test. Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in complex partial seizures.

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