New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer’s treatment: In silico identification, in vitro and in vivo validation

Anwar, Fareeha; Saleem, Uzma; Ahmad, Bashir; Ashraf, Muhammad; Rehman, Atta Ur; Froeyen, Matheus; Kee, Lee Yean; Abdullah, Iskandar; Mirza, Muhammad Usman; Ahmad, Sarfraz

doi:10.1016/j.compbiolchem.2020.107378

Cited by 20 publications

(13 citation statements)

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“…The prime goal of these preclinical toxicological studies of SF5, a candidate molecule for Alzheimer’s disease (AD), is to provide sufficient evidence of the biological safety of the drugs that possess drug-like properties. Easy and cost-effective synthesis of this SF5 drug molecule makes it more suitable as a drug-adhering property molecule ( Anwar et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In our recently published work, an extensive in silico approach was used to identify cost-effective AChE inhibitors for treating Alzheimer’s disease. A series of potent naphthalene-based AChE inhibitors were identified, synthesized, and evaluated for their in vitro and in vivo potentials against Alzheimer’s disease, in which one of these inhibitors is SF5 ( Anwar et al, 2020 ). Our previous study is the pilot study, and before the detailed in vivo study against Alzheimer’s disease, a brief toxicity profiling is necessary.…”

Section: Introductionmentioning

confidence: 99%

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Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

et al. 2022

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The U.S. National Research Council (NRC) introduced new approaches to report toxicity studies. The NRC vision is to explore the toxicity pathways leading to the adverse effects in intact organisms by the exposure of the chemicals. This study examines the toxicity profiling of the naphthalene-2-yl 2-chloro-5-dinitrobenzoate (SF5) by adopting the vision of NRC that moves from traditional animal studies to the cellular pathways. Acute, subacute, and developmental toxicity studies were assayed according to the Organization for Economic Cooperation and Development (OECD) guidelines. The stress response pathway, toxicity pathway, and adverse effects outcome parameters were analyzed by using their standard protocols. The results showed that the acute toxicity study increases the liver enzyme levels. In a subacute toxicity study, alkaline phosphatase (ALP) levels were raised in both male and female animals. SF5 significantly increases the normal sperm count in the male animals corresponding to a decrease in the abnormality count. Developmental toxicity showed the normal skeletal and morphological parameters, except little hydrocephalus was observed in developmental toxicity. Doses of 20 mg/kg in males and 4 mg/kg in females showed decreased glutathione (GSH) levels in the kidney and liver. MDA levels were also increased in the kidney and liver. However, histopathological studies did not show any cellular change in these organs. No statistical difference was observed in histamine levels, testosterone, nuclear factor erythroid two-related factor-2 (Nrf2), and nuclear factor-kappa B (NF-κB), which showed no initiation of the stress response, toxicity, and adverse effect pathways. Immunomodulation was observed at low doses in subacute toxicity studies. It was concluded that SF5 did not produce abrupt and high-toxicity levels in organs and biochemical parameters. So, it is safe for further studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

et al. 2022

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“…Additionally, many studies are available with oral administration of compounds closely related to SF1 via oral route for in vivo studies (Husain et al, 2012;Abbas et al, 2010;Masic et al, 2015). Subacute toxicity study was carried out to find out any abnormality in the organs after the repeated administration of the test compound at different dose levels (Abubakar et al, 2019;Anwar et al, 2020). In this study, four doses of SF1 (5, 10, 20, and 40 mg/kg) were selected for the subacute toxicity study.…”

Section: Discussionmentioning

confidence: 99%

“…Subacute toxicity study was carried out to find out any abnormality in the organs after the repeated administration of the test compound at different dose levels ( Abubakar et al, 2019 ; Anwar et al, 2020 ). In this study, four doses of SF1 (5, 10, 20, and 40 mg/kg) were selected for the subacute toxicity study.…”

Section: Discussionmentioning

confidence: 99%

Toxicity Evaluation of the Naphthalen-2-yl 3,5-Dinitrobenzoate: A Drug Candidate for Alzheimer Disease

et al. 2021

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The presented study was designed to probe the toxicity potential of newly identified compound naphthalen-2-yl 3,5-dinitrobenzoate (SF1). Acute, subacute toxicity and teratogenicity studies were performed as per Organization of economic cooperation and development (OECD) 425, 407, and 414 test guidelines, respectively. An oral dose of 2000 mg/kg to rats for acute toxicity. Furthermore, 5, 10, 20, and 40 mg/kg doses were administered once daily for 28 days in subacute toxicity study. Teratogenicity study was performed with 40 mg/kg due to its excellent anti-Alzheimer results at this dose. SF1 induced a significant rise in Alkaline Phosphatases (ALP), bilirubin, white blood cells (WBC), and lymphocyte levels with a decrease in platelet count. Furthermore, the reduction in urea, uric acid, and aspartate transaminase (AST) levels and an increase in total protein levels were measured in subacute toxicity. SF1 increased spermatogenesis at 5 and 10 mg/kg doses. Teratogenicity study depicted no resorptions, early abortions, cleft palate, spina bifida and any skeletal abnormalities in the fetuses. Oxidative stress markers (Superoxide dismutase (SOD), Catalase (CAT), and glutathione (GSH) were increased in all the experiments, whereas the effect on melanoaldehyde Malondialdehyde (MDA) levels was variable. Histopathology further corroborated these results with no change in the architectures of selected organs. Consequently, a 2000 mg/kg dose of SF1 tends to induce minor liver dysfunction along with immunomodulation, and it is well below its LD50. Moreover, it can be safely used in pregnancy owing to its no detectable teratogenicity.

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“…In our previous studies, a naphthalene derivative 4-phenyl-3,4-dihydrobeno-quinolin-2-one (SF3) was synthesized, and its in silico studies showed promising binding with the acetylcholinesterase (AChE) enzyme. 28 , 29 The previous study also showed its in vitro enzyme kinetic analysis against AChE. Before targeting their specific role in Alzheimer disease, toxicity studies are necessary to predict this compound’s hazardous effect.…”

Section: Introductionmentioning

confidence: 99%

Toxicological Screening of 4-Phenyl-3,4-dihydrobenzo[h]quinolin-2(1H)-one: A New Potential Candidate for Alzheimer’s Treatment

et al. 2021

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Toxicity studies are necessary for the development of a new drug. Naphthalene is a bicyclic molecule and is easy to derivatize. In our previous study, a derivative of naphthalene (4-phenyl,3,4-dihydrobenzoquinoline-2( H )one) was synthesized and reported its in vitro activity on different enzymes. This study was a probe to investigate the toxicity potential of that compound (SF3). Acute oral (425), subacute (407), and teratogenicity (414) studies were planned according to their respective guidelines given by organization of economic cooperation and development (OECD). Acute oral, subacute, and teratogenicity studies were carried out on 2000, 5–40, and 40 mg/kg doses. Blood samples were collected for hematological and biochemical analyses. Vital organs were excised for oxidative stress (superoxide dismutase, catalase, glutathione, and malondialdehyde) and histopathological analysis. LD 50 of SF3 was higher than 2000 mg/kg. In acute and subacute studies, levels of alkaline phosphates and aspartate transaminase were increased. Teratogenicity showed no resorptions, no skeletal or soft tissue abnormalities, and no cleft pallet. Oxidative stress biomarkers were close to the normal, and no increase in the malondialdehyde level was seen. Histopathological studies revealed normal tissue architecture of the selected organs, except kidney, in acute oral and subacute toxicity studies at 40 mg/kg. The study concluded that SF3 is safer if used as a drug.

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New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer’s treatment: In silico identification, in vitro and in vivo validation

Cited by 20 publications

References 40 publications

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

Toxicity Evaluation of the Naphthalen-2-yl 3,5-Dinitrobenzoate: A Drug Candidate for Alzheimer Disease

Toxicological Screening of 4-Phenyl-3,4-dihydrobenzo[h]quinolin-2(1H)-one: A New Potential Candidate for Alzheimer’s Treatment

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