Recent applications of hydantoin and thiohydantoin in medicinal chemistry.

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.

/pdf/the-histamine-h3r-antagonist-dl77-attenuates-autistic-5eq9awc1so.pdf

The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.

In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865–1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin’s anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937–1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin’s activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 μM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.

Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action

Baicalein is one of the major ﬂavonoids found in the rootof Scutellaria baicalensis Georgi. Previous studies suggest that bai-calein displays protective effect on experimental cardiac modelsin vitro and in vivo. However, the mode of action remains unclear.Here, we showed that baicalein conferred cardioprotective effectagainst oxidative stress-induced cell injury in H9c2 cells and humanembryonic stem cells-derived cardiomyocytes. Immunoprecipitationwith anti-NF-E2–related factor 2 (Nrf2) antibody in baicalein-treatedcells demonstrated that baicalein effectively disrupted the associationbetween Nrf2 and Kelch-like epichlorohydrin-associated protein1 (Keap1). In addition, the unbounded Nrf2 translocated from cyto-plasm to nucleus and increased Nrf2/heme oxygenase-1 (HO-1) con-tent in a time-dependent manner. Moreover, antioxidant responseelement transcriptional activity was enhanced by baicalein treatment,and the Nrf2 siRNA transfection could block the cytoprotectiveeffect of baicalein. Taken together, these results demonstrate thatbaicalein protected cardiomyocytes against oxidative stress-inducedcell injury through the Nrf2/Keap1 pathway.Key Words: baicalein, cardioprotection, oxidative stress, Nrf2(J Cardiovasc Pharmacol 2015;65:39–46)

Cytoprotection of baicalein against oxidative stress-induced cardiomyocytes injury through the Nrf2/Keap1 pathway.

https://hal-amu.archives-ouvertes.fr/hal-01425032/document

Amine-alkyl derivatives of hydantoin: new tool to combat resistant bacteria.

Synthesis, α1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin

Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α1-adrenoceptor affinities

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Synthesis, α1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin

Antiarrhythmic properties of phenylpiperazine derivatives of phenytoin with α1-adrenoceptor affinities