Evaluation of the Lipophilicity of Angularly Condensed Diquino- and Quinonaphthothiazines as Potential Candidates for New Drugs.

Lipophilicity is one of the most important properties of compounds required to estimate the absorption, distribution, and transport in biological systems, in addition to solubility, stability, and acid-base nature. It is crucial in predicting the ADME profile of bioactive compounds. The study assessed the usefulness of computational and chromatographic methods (thin-layer chromatography in a reversed-phase system, RP-TLC) for estimating the lipophilicity of 21 newly synthesized compounds belonging to diquinothiazines and quinonaphthiazines. In order to obtain reliable values of the relative lipophilicities of diquinothiazines and quinonaphthiazines, the partition coefficients obtained using different algorithms such as AlogPs, AClogP, AlogP, MLOGP, XLOGP2, XLOGP3, logP, and ClogP were compared with the chromatographic RM0 values of all the tested compounds measured by the experimental RP-TLC method (logPTLC). Additionally, logPTLC values were also correlated with other descriptors, as well as the predicted ADME and drug safety profiling parameters. The linear correlations of logPTLC values of the tested compounds with other calculated molecular descriptors such as molar refractivity, as well as ADME parameters (Caco-2 substrates, P-gp inhibitors, CYP2C19, and CYP3A4) generally show poor predictive power. Therefore, in silico ADME profiling can only be helpful at the initial step of designing these new candidates for drugs. The compliance of all discussed diquinothiazines and naphthoquinothiazines with the rules of Lipinski, Veber, and Egan suggests that the tested pentacyclic phenothiazine analogs have a chance to become therapeutic drugs, especially orally active drugs.

Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy.

Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.

Study of the Lipophilicity and ADMET Parameters of New Anticancer Diquinothiazines with Pharmacophore Substituents.

Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as RM0, was determined experimentally by the RP-TLC method using RP18 plates and acetone-TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (RM0) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process.

A Computational Study of Phenothiazine Derivatives as Acetylcholinesterase Inhibitors Targeting Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a neurodegenerative disorder that affects learning, memory and behavioral turbulence in elderly patients. Acetylcholinesterase (AChE) inhibitors act as anti-Alzheimer's agents. Phenothiazine derivatives are considered momentous anti-Alzheimer's agents because of their AChE inhibitory activity. The elevated levels and increased expression of this protein have been associated with Alzheimer's disease. Coumarin-fused phenothiazines have emerged as significant anti-Alzheimer's agents due to their notable receptor inhibitory activity. OBJECTIVE: Some unique phenothiazine analogs were designed, and computational studies were conducted to explore their inhibitory activity against the AChE enzyme (PDB id: 4EY7) by using the Schrodinger suite-2019-4. METHODS: Docking studies were conducted by using the Glide module; binding free energies were calculated by means of the Prime MM-GBSA module, and Molecular dynamics (MD) simulation was performed by using the Desmond module of the Schrodinger suite. Glide scores were used to find out the binding affinity of the ligands with the target 4EY7. RESULTS: The compounds exhibited enhanced hydrophobic interactions and formed hydrogen bonds, effectively impeding Acetylcholinesterase. The Glide scores for the compounds ranged from -13.4237 to -8.43439, surpassing the standard (Donepezil) with a score of -16.9898. Interestingly, a positive value was obtained for the MM-GBSA binding of the potent inhibitor. To gain insights into the dynamic behavior of the protein A8, molecular dynamics (MD) simulations were employed. CONCLUSION: Based on the results, the study concludes that phenothiazine derivatives show promise as acetylcholinesterase inhibitors. Compounds with notable Glide scores are poised to exhibit significant anti-Alzheimer's activity, suggesting their potential therapeutic efficacy. Further in vitro and in vivo investigations are warranted to validate and explore the therapeutic potentials of these compounds.

Spectroscopic studies under properties of chlorpromazine conjugated to gold nanoparticles.

Scientific studies have demonstrated that conjugates of anticancer drugs with metal nanoparticles (MeNPs) lead to a more effective deactivation of tumor cells compared to free drugs. Similarly, it has been established that conjugates of antibiotics with MeNPs exhibit higher biocidal activity against bacteria than their unbound counterparts. However, limited information is available regarding conjugates formed from drugs other than anticancer and antibiotics. Therefore, our research aims to develop synthesis methods for conjugates of chlorpromazine (CPZ), a neuroleptic, with gold nanoparticles (AuNPs). CPZ-AuNP conjugates were prepared through a ligand exchange reaction conducted on the surface of quasi-spherical, negatively charged citrate-stabilized TC-AuNPs with an average size of 55 ± 5 nm. UV-vis spectroscopy was employed to determine the stability range of the conjugates under controlled conditions of pH and ionic strength. Based on electrokinetic measurements, it was observed that the zeta potential of CPZ-AuNP conjugates strongly depends on the amount of CPZ adsorbed on the TC-AuNP surface. Additionally, the conjugates exhibited an isoelectric point at pH 8.8. Surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared absorption spectroscopy (SEIRA) were employed to elucidate the adsorption structure of CPZ on TC-AuNPs. The interpretation of the spectra was conducted based on the Raman and FTIR spectra of CPZ, along with calculations performed using Density Functional Theory (DFT). The results indicated that CPZ primarily interacts with the TC-AuNP surface through the angularly oriented phenothiazine ring and the propylene bridge. Furthermore, it was demonstrated that the C-N-C fragment is perpendicular to the surface of the TC-AuNP with which it interacts. The findings from this analysis suggest the potential for further research on the use of these conjugates in biomedical applications.

Splenic congestion associated with acepromazine administration in dogs / Congestão esplênica associada à aplicação de acepromazina em cães

The effects splenic dilatation induced by acepromazine in a prospective, randomized study. Thirtythree adult mongrel dogs were divided into two groups designated as AG (acepromazine 0.05 mg/kg, i.v., n = 23) and CG (0.9 percent sodium chloride administered at a similar volume, n = 10). In both groups underwent sonographic examinations before (T0) and fifteen minutes (T15) after drug injection. The thickness spleen and splenic vein width were measured. Higher thickness was found in the AG group at T15 (2.47 cm) when compared to that at T0 (2.06 cm, p = 0.016), while the T0 (2.33 cm) and T15 (2.39 cm) measures did not differ within the CG group. Moreover, the splenic vein width was higher (p = 0.013) at T15 than at T0 in the AG group. Based on results of this study, we concluded that acepromazine, in doses of 0.05 mg/kg, promotes splenomegaly in dogs after fifteen minutes of the injection.

Foram avaliados os efeitos de dilatação esplênica induzidos pela acepromazina em estudo do tipo prospectivo e randomizado. Trinta e três cães foram distribuídos em dois grupos designados como GA (acepromazina 0,05 mg/kg, i.v., n = 23) e GC (solução de cloreto de sódio 0,9 por cento em volume semelhante ao GA, i.v., n = 10). Em ambos os grupos foi realizada ultrassonografia abdominal previamente à aplicação das substâncias (T0) e após 15 minutos (T15). A espessura do baço e a largura da veia esplênica foram mensuradas. Foi verificada maior espessura esplênica no GA no T15 (2,47 cm) quando comparado a T0 (2,06 cm, p = 0,016), enquanto no GC não houve diferença significativa, sendo T0 (2,33 cm) e T15 (2,39 cm). Ainda, a largura da veia esplênica foi maior no T15 (p = 0,013) comparado a T0no GA. Baseado nos resultados encontrados, pode-se concluir que a acepromazina na dose de 0,05 mg/kg induz a esplenomegalia em cães após 15 minutos da aplicação.

Comparison of the sedative effects of morphine, meperidine or fentanyl, in combination with acepromazine, in dogs / Comparação dos efeitos sedativos da morfina, meperidina ou fentanil, associados à acepromazina, em cães

This study aimed to compare the sedative effects of morphine, meperidine and fentanyl, in combination with acepromazine (ACP) and their effects on physiologic values in dogs. Six healthy beagle dogs were randomly assigned to four treatments with 7-day washout intervals. In three treatments, ACP (0.05mg kg-1) was administered and 20 minutes later, the dogs received administration of 0.5mg kg-1 of morphine (ACPMOR), 5mg kg-1 of meperidine (ACPMEP) or 5µg kg-1 of fentanyl (ACPFEN). In treatment ACP HD MOR, 0.1mg kg-1 of ACP was administered in combination with 0.5mg kg-1 of morphine. All drugs were administered intravenously. Sedation scores were evaluated by a numeric descriptive scale (NDS: 0-3) and a simple numeric scale (SNS: 0-10). All variables were evaluated for 120 minutes. The administration of ACP caused mild to moderate sedation. Sedation was improved in all treatments after opioid administration, but significant differences were detected only in ACPMOR and ACP HD MOR. More dogs presented intense sedation (NDS=3.0) after administration of morphine (3/6 and 4/6 dogs in ACPMOR and ACP HD MOR versus 1/6 in other treatments). Duration of sedation was longer in ACPMOR and ACP HD MOR. Mild to moderate decreases in blood pressure, respiratory rate and temperature were observed in all treatments but decreased HR was observed only in ACPMOR and ACP HD MOR. No significant differences were observed in the aforementioned variables when twice the dose of ACP was used (treatment ACP HD MOR). Under the conditions of this study, administration of morphine, in combination with ACP, results in greater and longer sedation than meperidine and fentanyl. Increasing the dose of ACP, in combination with morphine, does not improve the degree of sedation. All combinations used were considered to be safe for healthy dogs.

O presente estudo objetivou comparar o efeito sedativo da morfina, meperidina e fentanil associados à acepromazina (ACP) e seus efeitos sobre as variáveis fisiológicas de cães. Seis cães Beagle hígidos foram aleatoriamente submetidos a quatro tratamentos com intervalo de 7 dias. Em três tratamentos, foi administrada ACP (0,05mg kg-1) e, após 20 minutos, 0,5mg kg-1 de morfina (ACPMOR), 5mg kg-1 de meperidina (ACPMEP) ou 5µg kg-1 de fentanil (ACPFEN). No tratamento ACP DA MOR, a dose de 0,1mg kg-1 de ACP foi associada a 0,5mg kg-1 de morfina. Todos os fármacos foram administrados pela via IV. Escores de sedação foram avaliados pela escala numérica descritiva (END: 0-3) e escala numérica simples (ENS: 0-10). Todas as variáveis foram avaliadas durante 120 minutos. A administração da ACP causou sedação leve à moderada. A sedação foi intensificada em todos os tratamentos após a administração do opioide, mas diferença significativa foi observada somente em ACPMOR e ACP DA MOR. Um número maior de cães apresentou sedação intensa (END=3,0) após a administração da morfina (3/6 e 4/6 cães em ACPMOR e ACP DA MOR versus 1/6 nos demais tratamentos). A duração do efeito sedativo foi mais longa em ACPMOR e ACP DA MOR. Houve redução leve a moderada na pressão arterial, frequência respiratória e temperatura em todos os tratamentos e redução significativa da frequência cardíaca somente nos tratamentos ACPMOR e ACP DA MOR. Não houve diferenças significativas nas variáveis estudadas quando o dobro da dose de ACP foi utilizada (tratamento ACP DA MOR). Nas condições deste estudo, a administração da morfina, em associação à ACP, resulta em sedação de maior intensidade e duração do que a meperidina e o fentanil. O aumento na dose de ACP, em associação à morfina, não intensifica o grau de sedação. Todas as associações foram consideradas seguras para cães hígidos.

Influence of acepromazine on the cardiovascular actions of dobutamine in isoflurane-anesthetized horses / Influência da acepromazina sobre os efeitos cardiovasculares da dobutamina em cavalos anestesiados com isofluorano

The influence of acepromazine (ACP) on the effectiveness of dobutamine (DBT) in increasing blood pressure during isoflurane (ISO) anesthesia was evaluated in six horses. On separate occasions, the horses were randomly assigned to receive NaCl 0.9 percent (Control), ACP 0.025mg kg-1 and ACP 0.05mg kg-1. The experimental treatment was administered prior to induction of anesthesia. Maintenance of anesthesia was performed under conditions of normocapnia with ISO in oxygen. Dobutamine was administered at progressively increasing infusion rates until mean arterial pressure (MAP) reached 70mmHg or until a maximum infusion rate of 5.0µg kg-1 min-1. Compared with baseline, DBT increased heart rate, systolic, diastolic and mean blood pressures in all treatments. However, these variables did not differ among treatments. The target MAP (70mmHg) was not reached in 2/6, 2/5 and 0/6 horses in the Control, ACP0.025 and ACP0.05 treatments, respectively. The mean dose of DBT to achieve target MAP was 3.5±1.8, 3.7±1.6 and 2.7±1.4µg kg-1 min-1 in the Control, ACP0.025 and ACP0.05 treatments, respectively (P>0.05). Under the conditions of this study, premedication with ACP does not interfere with the effectiveness of DBT in increasing blood pressure in horses anesthetized with ISO.

A influência da acepromazina (ACP) sobre a capacidade da dobutamina (DBT) em elevar a pressão arterial durante a anestesia com isofluorano (ISO) foi avaliada em seis equinos. Em ocasiões diferentes, os animais receberam aleatoriamente NaCl 0,9 por cento (Controle), ACP 0,025mg kg-1 e ACP 0,05mg kg-1. O tratamento experimental foi administrado previamente à indução da anestesia. A manutenção da anestesia foi realizada em condições de normocapnia com ISO em oxigênio. A administração de DBT foi iniciada em doses progressivamente crescentes até que o valor de pressão arterial média (PAM) atingisse 70mmHg ou até a dose máxima de 5,0µg kg-1 min-1. Comparado ao basal, a administração da DBT resultou em elevação na frequência cardíaca e pressões arteriais sistólica, diastólica e média em todos os tratamentos. Porém, não houve diferença entre os tratamentos nessas variáveis. A PAM alvo (70mmHg) não foi atingida em 2/6, 2/5 e 0/6 animais dos tratamentos Controle, ACP0.025 e ACP0.05, respectivamente. A dose média de DBT para a PAM alvo foi de 3,5±1,8; 3,7±1,6 e 2,7±1,4µg kg-1 min-1 no Controle, ACP0.025 e ACP0.05, respectivamente (P>0,05). Nas condições deste estudo, o pré-tratamento com ACP não interfere na eficácia da DBT em elevar a pressão arterial de cavalos anestesiados com ISO.

Efeitos de compostos naturais, sintéticos e da fototerapia antifúngica sobre Candida tropicalis resistente ao fluconazol / Effects of natural compounds, synthetic and herbal medicine on Candida tropicalis antifungal fluconazole-resistant

A candidíase é uma infecção oportunista provocada por diversas espécies de fungos do gênero Candida, frequentemente encontrados integrando a microbiota, da superfície cutânea, no trato gastrointestinal e cavidades mucosas do ser humano desde o seu nascimento. A incidência das infecções fúngicas sistêmicas têm aumentado consideravelmente nas últimas décadas em função do grande número de pacientes com SIDA, a grande quantidade de transplantes e condições crônicas como o câncer, a terapia prolongada com imunossupressores e o uso de agentes corticosteroides. Além disso, a exposição prolongada aos antifúngicos azólicos promove a seleção de patógenos resistentes. No presente estudo avaliou-se a atividade antifúngica do complexo Rutênio-pirocatecol (RPC) frente a um isolado clinico de Candida tropicalis resistente ao fluconazol. A metodologia empregada para os testes de susceptibilidade foi de acordo com o documento M27-A3 do National Committee for Clinical Laboratory Standards (NCCLS, 2008). Esplenócitos de camundongos Balb/c foram obtidos de forma asséptica para avaliar a citotoxicidade do composto para células de mamíferos. O estresse oxidativo promovido pelo composto foi avaliado através da reação ao ácido tiobarbitúrico (TBARS) e ensaios de fluorescência com a sonda diclorodihidrofluoresceína diacetato (DCFH2DA). O Calcofluor White foi empregado para avaliar a integridade da parede celular. A análise ultraestrutural foi realizada através da microscopia eletrônica de varredura e transmissão. Os resultados encontrados para os testes de atividade antifúngica foram analisados através do teste estatístico ANOVA e pós-teste Dunnett. Os resultados encontrados para os testes de atividade antifúngica do RPC mostraram uma Concentração Inibitória de 50% (IC50) de 20,3 μM, enquanto em esplesnócitos a concentração efetiva de 50% foi de 325 μM mostrando um índice de seletividade igual a 16...

Candidiasis is an opportunistic infection caused by several species of fungi of the genus Candida, often found is the microbiota, on the skin, gastrointestinal tract and mucous cavities of the human beings birth. The incidence of systemic fungal infections have increased considerably in recent decades due to the large number of AIDS patients, the large number of transplants and chronic conditions such as cancer, prolonged therapy promotes the selection of resistant pathogen with immunosuppressant and corticosteroid agents. Also prolonged exposure azole antifungals to make them strong candidates for patients resistance. In the present study we evaluated the antifungal activity of Ruthenium-pyrocatechol complex (RPC) against a clinical isolate of Candida tropicalis resistant to fluconazole. The methodology for susceptibility testing was in accordance with the M27-A3 document of there National Committee for Clinical Laboratory Standards (NCCLS, 2008). Splenocytes from Balb/c mice were obtained aseptically to evaluate the cytotoxicity of the compound to mammalian cells. Oxidative stress caused by the compound was assessed by reaction to thiobarbituric acid (TBARS) and fluorescence assays with the probe diclorodihidrofluoresceína diacetate (DCFH2DA). The Calcofluor White was used to evaluate the integrity of the cell wall. The ultrastructural analysis was performed by scanning and transmission electron microscopy. The results for the antifungal activity tests were analyzed using ANOVA and pos-test Dunnett test statistic. The results for the tests of antifungal activity of the RPC showed a 50% inhibitory concentration (IC50) of 20.3 μM while in splenocytes the 50% effective concentration was 325 μM showing a selectivity index of 16...

Inactivación de la dihidrolipoamida deshidrogenasa de Trypanosoma cruzi por fenotiazinas en presencia de citocromo c y peróxido de hidrógeno: efectos de los antioxidantes / Trypanosoma cruzi dihydrolipoamide dehydrogenase is inactivated by phenothiazines in the presence of cytochrome c and hydrogen peroxide: effects of antioxidants

El citocromo c catalizó la oxidación de las fenotiazinas (FTZ) en presencia de peróxido de hidrógeno. La formación del radical catiónico de promazina (PZ+.) se demostró por espectrofo-tometría y por su conversión a promazina sulfóxido La dihidrolipoamida deshidrogenasa (LADH) del Trypanosoma cruzi es inhibida irreversiblemente por el sistema citocromo c/H2O2 complementado con fenotiazinas. La inactivación de la LADH del parásito varía según la estructura de las FTZ, el tiempo de incubación del sistema pro-oxidante con la LADH, y la presencia de un antioxidante supresor de radicales FTZ+. Entre las 12 FTZ ensayadas, la promazina (PZ), tioridazina (TRDZ) y trimeprazina (TMPZ) fueron las más efectivas produciendo inactivaciones de 82 por ciento,76 por ciento y 72 por ciento, respectivamente, a los 90 min de incubación. El efecto de PZ (con grupo alquilamino en la posición N 10) disminuyó por modificación de su estructura en la posición 2 (efecto inactivante de PZ > cloropromazina (CPZ) > propionilpromazina (PPZ) > trifluopromazina (TFPZ) o en la posición 10 ( efecto inactivante de PZ > TMPZ > prometazina (PMTZ).El efecto de las FTZ con sustituyente piperidinil en N 10 dependió del grupo de la posición 2 ( SCH3, en TRDZ de mayor efecto; CN, en propericiazina (PCYZ), la de menor efecto entre las FTZ estudiadas). Parece que la presencia del sustituyente piperazinil en posición N 10 no tiene función importante en el efecto inactivante de las FTZ, el cual dependió de la estructura del grupo en la posición 2. El efecto de los compuestos con Cl en posición 2 (CPZ, procloroperazina (PCP), perfenazina (PFZ)) fue mayor que el obtenido con los compuestos CF3 (TFPZ, trifluoroperazina (TFP), flufenazina (FFZ), e independiente de la estructura del sustituyente N 10.El efecto de las FTZ sobre la LADH de T. cruzi depende, por lo menos en parte, de la estabilidad de los radicales FTZ+. generados por la actividad peroxidasa. La LADH T c, en comparación con la LADH de mamífero...

Cytochrome c catalyzed the oxidation of phenothiazines (PTZ) in the presence of hydrogen peroxide. The transient formation of the promazine radical cation (PZ+.) has been demonstrated by light absorption measurements as well as by its conversión to promazine sulfoxide. Trypanosoma cruzi dihydrolipoamide dehydrogenase (LADH T c) was irreversibly inhibited by treatment with cytochrome c (cyt c)/H2O2 system supplemented with PTZ. LADH T c inactivation depended on a) The PTZ structure b) Time of incubación with the complete oxidant system c) The presence of an antioxidant that intercept free radicals. PZ, thioridazine (TRDZ) and trimeprazine (TMPZ), were the most effective systems out of twelve PTZ studied, with inactivation values of 82, 76 and 72%, respectively, after 90 min of incubation. LADH T c inactivation by PZ (with alkylamine substituent at N 10 position) decreased by its structural modification at 2 position (inactivation PZ > chlorpromazine (CPZ) > propionylpromazine (PPZ)>trifluopromazine (TFPZ)) or at N 10 position (inactivation PZ > TMPZ > promethazine (PMTZ)) PTZ activity with piperidinyl substituent at N10 position depended on the group at 2 position (TRDZ, with thiomethyl group, has high inactivating effect on LADH T c; propericyazine (PCYZ), with cyano group, is much less active). Apparently, piperazinyl substituent at the N10 position on the phenothiazine have not an important function in the compound's inactivating effect on LADH T c. The effect of PTZ with Cl at 2 position (CPZ, prochlorperazine (PCP), perphenazine (PFZ)) was higher than the effect of compounds with CF3 in the same position (TFPZ,trifluoperazine (TFP),fluphenazine (FFZ) ) independent on the structure of substituents at N10 position. Production of PTZ+. radicals was essential for LADH T c inactivation and this effect depended on the stability of these free radicals. Comparision of inactivation values for LADH T c and mammalian LADH demonstrated...