Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds.

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Novel Piperazine Amides of Cinnamic Acid Derivatives as Tyrosinase Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180420105652 ◽

2018 ◽

Vol 16 (1) ◽

pp. 36-44 ◽

Cited By ~ 3

Author(s):

Zehra Tuğçe Gür ◽

Fatma Sezer Şenol ◽

Suhaib Shekfeh ◽

İlkay Erdoğan Orhan ◽

Erden Banoğlu ◽

...

Keyword(s):

Cinnamic Acid ◽

Active Site ◽

Agaricus Bisporus ◽

Biological Activities ◽

Docking Simulation ◽

Cinnamic Acid Derivatives ◽

In Silico Docking ◽

Amide Derivatives ◽

Tyrosinase Inhibitors ◽

Further Development

Background: A series of novel cinnamic acid piperazine amide derivatives has been designed and synthesized, and their biological activities were also evaluated as potential tyrosinase inhibitors. Methods: Compounds 9, 11 and 17 showed the most potent biological activity (IC50 = 66.5, 61.1 and 66 µM, respectively). In silico docking simulation was performed to position compound 11 into the Agaricus bisporus mushroom tyrosinase’s active site to determine the putative binding interactions. Results and Conclusion: The results indicated that compound 11 could serve as a promising lead compound for further development of potent tyrosinase inhibitors.

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Tetramethylcyclopropyl Analogue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and Evaluation of Anticonvulsant Activity of Its Amide Derivatives

Journal of Medicinal Chemistry ◽

10.1021/jm0498351 ◽

2004 ◽

Vol 47 (17) ◽

pp. 4316-4326 ◽

Cited By ~ 24

Author(s):

Eyal Sobol ◽

Meir Bialer ◽

Boris Yagen

Keyword(s):

Valproic Acid ◽

Antiepileptic Drug ◽

Anticonvulsant Activity ◽

Acid Synthesis ◽

Amide Derivatives

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MONITORING OF ANTICONVULSANT DRUG SIDE EFFECTS IN OUTPATIENTS WITH EPILEPSY

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2018.v10s1.67 ◽

2018 ◽

Vol 10 (1) ◽

pp. 303

Author(s):

Santi Purna Sari ◽

Natasha Kurnia Salma S ◽

Alfina Rianti

Keyword(s):

Valproic Acid ◽

Side Effects ◽

Medical Records ◽

Side Effect ◽

Anticonvulsant Drug ◽

Secondary Data ◽

Drug Side Effects ◽

Inclusion Criteria ◽

Descriptive Data ◽

Effect Monitoring

Objective: This study aimed to monitor the side effects of carbamazepine, phenytoin, and valproic acid, and combinations of these drugs in adultpatients with epilepsy, to raise awareness of the importance of drug side effect monitoring in hospitals.Methods: In this prospective study, descriptive data were collected from patients who met the inclusion criteria of complete samples. Primary datawere obtained using questionnaires, secondary data were collected from medical records, and analyses were performed using the Naranjo algorithm.Results: Among the 54 included patients, 38 (70.37%) of them experienced drug side effects, and the most frequently observed side effect occurredin 48.15% of study subjects.Conclusion: No correlation was identified between side effects and age (p=0.903) or gender (p=1.000).

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Nonclassical Biological Activities of Quinolone Derivatives

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3302n ◽

2011 ◽

Vol 15 (1) ◽

pp. 52 ◽

Cited By ~ 19

Author(s):

Mohsen Daneshtalab ◽

Abeer Ahmed

Keyword(s):

Mammalian Cells ◽

Antibacterial Agents ◽

Biological Activities ◽

Antiviral Agent ◽

Bioactive Molecules ◽

Structural Modifications ◽

Further Development ◽

Derivatives Of ◽

Ns5b Polymerase

Quinolones are considered as a big family of multi-faceted drugs; their chemical synthesis is flexible and can be easily adapted to prepare new congeners with rationally devised structures. This is shown by the description of many thousands of derivatives in the literature. Scientists could accurately describe their QSAR, which is essential for effective drug design. This also gave them the chance to discover new and unprecedented activities, which makes quinolones an endless source of hope and enables further development of new clinically useful drugs. Quinolones are among the most common frameworks present in the bioactive molecules that have dominated the market for more than four decades. Since 1962, 4(1H)-quinolone-3-carboxylic acid derivatives are widely used as antibacterial agents. Quinolones have a broad and potent spectrum of activity and are also used as second-line drugs to treat tuberculosis (TB). Recently, quinolones have been reported to display “nonclassical” biological activities, such as antitumor, anti-HIV-1 integrase, anti- HCV-NS3 helicase and -NS5B-polymerase activities. The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent and/or an antiviral agent. Indeed, quinolones’ antimicrobial action is distinguishable among antibacterial agents, because they target different type II topoisomerase enzymes. Many derivatives of this family show high activity against bacterial topoisomerases and eukaryotic topoisomerases, and are also toxic to cultured mammalian cells and in vivo tumor models. Moreover, quinolones have shown antiviral activity against HIV and HCV viruses. In this context the quinolones family of drugs seem to link three different biological activities (antibacterial, anticancer, and the antiviral profiles) and the review will also provide an insight into the different mechanisms responsible for these activities among different species. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Valproic acid: an anticonvulsant drug with potent antinociceptive and anti-inflammatory properties

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-013-0853-4 ◽

2013 ◽

Vol 386 (7) ◽

pp. 575-587 ◽

Cited By ~ 39

Author(s):

José Christian Machado Ximenes ◽

Danilo de Oliveira Gonçalves ◽

Rafaelly Maria Pinheiro Siqueira ◽

Kelly Rose Tavares Neves ◽

Gilberto Santos Cerqueira ◽

...

Keyword(s):

Valproic Acid ◽

Anticonvulsant Drug ◽

Anti Inflammatory

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The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

Molecular Pharmacology ◽

10.1124/mol.106.030601 ◽

2006 ◽

Vol 71 (3) ◽

pp. 884-892 ◽

Cited By ~ 25

Author(s):

J. A. Shimshoni ◽

E. C. Dalton ◽

A. Jenkins ◽

S. Eyal ◽

K. Ewan ◽

...

Keyword(s):

Central Nervous System ◽

Valproic Acid ◽

Nervous System ◽

Growth Cone ◽

Neuronal Growth ◽

Amide Derivatives ◽

Neuronal Growth Cone

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Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid.

Clinical Chemistry ◽

10.1093/clinchem/31.1.60 ◽

1985 ◽

Vol 31 (1) ◽

pp. 60-64 ◽

Cited By ~ 98

Author(s):

J Barré ◽

J M Chamouard ◽

G Houin ◽

J P Tillement

Keyword(s):

Valproic Acid ◽

Human Serum Albumin ◽

Binding Sites ◽

Plasma Proteins ◽

Equilibrium Dialysis ◽

Anticonvulsant Drug ◽

Drug Binding ◽

Binding Characteristics ◽

Affinity Constants ◽

Number Of Binding Sites

Abstract Equilibrium dialysis, ultrafiltration, and ultracentrifugation were compared to determine their reliability and applicability in the study of binding of an anticonvulsant drug, valproic acid, by plasma proteins. We studied drug binding with pooled serum and with solutions of human serum albumin at physiological concentrations. We compared binding characteristics such as number of binding sites, affinity constants, and percent of binding as measured by each method in the therapeutic range for valproic acid. Results by ultracentrifugation differed from those by equilibrium dialysis and ultrafiltration, which agreed reasonably well with each other.

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3-Sulfamoylmethyl-l, 2-benzisoxazole, a new type of anticonvulsant drug: Pharmacological profile

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)66864-2 ◽

1979 ◽

Vol 29 ◽

pp. 30

Author(s):

Yoshinobu Masuda ◽

Tadahiko Karasawa ◽

Yuko Shiraishi ◽

Misako Hori ◽

Kouichi Yoshida ◽

...

Keyword(s):

Anticonvulsant Drug ◽

Pharmacological Profile ◽

New Type

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Cell wall integrity is compromised under temperature stress in Schizosaccharomyces pombe expressing a valproic acid-sensitive vas4 mutant

Scientific Reports ◽

10.1038/s41598-021-92466-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sen Qiao ◽

Xiaofang Luo ◽

Hui Wang ◽

Yue Fang ◽

Lili Zhang

Keyword(s):

Valproic Acid ◽

Cell Wall ◽

Temperature Stress ◽

Histone Deacetylases ◽

Target Genes ◽

Trichostatin A ◽

Anticonvulsant Drug ◽

Cell Wall Integrity ◽

Loss Of Function ◽

Copii Vesicles

AbstractValproic acid (VPA) is widely used as a eutherapeutic and safe anticonvulsant drug, but the mechanism is not well elucidated. Histone deacetylases (HDACs) were first identified as direct targets of VPA. Many loss-of function mutants in S. pombe have been shown to be VPA sensitive but not sensitive to other HDAC inhibitors, such as sodium butyrate or trichostatin A (TSA). This difference suggests that there are multiple VPA target genes. In the current study, we isolated a VPA-sensitive (vas) mutant, vas4-1, and cloned the VPA target gene vas4+/vrg4+ by performing complementation experiments. The vas4+/vrg4+ gene encodes a putative Golgi GDP-mannose transporter, Vrg4, which is highly homologous with ScVrg4p. Physiological experiments indicated that SpVrg4p is involved in maintaining cell wall integrity (CWI) under high- or low-temperature stress. The results of a coimmunoprecipitation assay suggested that SpVrg4p may be transferred from the ER to the Golgi through SpGot1p loaded COPII vesicles, and both single and double mutations (S263C and A271V) in SpVrg4p compromised this transfer. Our results suggested that CWI in S. pombe is compromised under temperature stress by the VPA-sensitive vas4 mutant.

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