A Molecular Generative Model of COVID-19 Main Protease Inhibitors Using Long Short-Term Memory-Based Recurrent Neural Network.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious threat to public health and prompted researchers to find anti-coronavirus 2019 (COVID-19) compounds. In this study, the long short-term memory-based recurrent neural network was used to generate new inhibitors for the coronavirus. First, the model was trained to generate drug compounds in the form of valid simplified molecular-input line-entry system strings. Then, the structures of COVID-19 main protease inhibitors were applied to fine-tune the model. After fine-tuning, the network could generate new molecular structures as novel SARS-CoV-2 main protease inhibitors. Molecular docking exhibited that some generated compounds have the proper affinity to the active site of the protease. Molecular Dynamics simulations explored binding free energies of the compounds over simulation trajectories. In addition, in silico absorption, distribution, metabolism, and excretion studies showed that some novel compounds could be formulated as orally active agents. Based on molecular docking and molecular dynamics simulation studies, compound AADH possessed significant binding affinity and presumably inhibition against the SARS-CoV-2 main protease enzyme. Therefore, the proposed deep learning-based model was capable of generating promising anti-COVID-19 drugs.

Amphotericin B Pharmacokinetics: Inter-strain Differences in Rats Following Intravenous Administration of the Most Commonly Marketed Formulations of the Drug.

Background: Amphotericin B (AmB) is the first-line drug to treat invasive fungal infections. However, its delivery to the body and clinical use faces many challenges because of its poor solubility, poor pharmacokinetics, and severe nephrotoxicity. Objectives: Due to the necessity for designing safer and more effective nanocarriers for AmB and the importance of preclinical pharmacokinetic studies in evaluating these novel drug delivery systems, the present study was framed to explore the influence of rat strain on the pharmacokinetic profile of this drug. Methods: Twenty-four Wistar and Sprague-Dawley (SD) rats were intravenously injected with 1 mg/kg AmB as Fungizone or AmBisome, which are the two most commonly marketed formulations of the drug. Blood samples were collected before and at regular intervals up to 24 h after administration. Drug concentration was analyzed by a validated HPLC method, and pharmacokinetic parameters were determined by the non-compartmental method. Results: Irrespective of the type of formulation, the AUC0-t and AUC0-∞ values were significantly higher (P < 0.001), and Cl as an important PK parameter was markedly lower (P < 0.001) in SD rats compared to the Wistar strain. For Fungizone, the mean Cl values in SD and Wistar rats were 206.90 and 462.95 mL/h/kg (P < 0.001), respectively. The apparent volume of distribution (Vss) was also lower in SD rats compared to Wistar; however, for AmBisome, the difference in Vss was not statistically significant. Our further investigation suggested that the higher amount of total protein in the SD strain may justify the higher plasma concentrations and lower Cl and Vss of amphotericin B in this strain compared to the Wistar strain. Conclusions: Overall, following intravenous administration of AmB, there were significant differences in the pharmacokinetic parameters of the drug between two rat strains for both formulations. The obtained data is important for correctly interpreting experimental data from different research groups.

Absence of Asymptomatic Malaria Reservoirs in an Area with a Previous History of Local Malaria Transmission: A Successful Experience in Line with the Malaria Elimination Program in Iran.

Background: Asymptomatic malaria is a major challenge to be addressed in the implementation of the malaria elimination program. The main goal of the malaria surveillance system in the elimination phase is to identify reliably all the positive cases of malaria reliably (symptomatic and asymptomatic) in the shortest possible time. This study focused on the monitoring of asymptomatic malaria reservoirs in areas where local transmission had been previously established. Methods: It was a case-study approach that was conducted in the Anarestan area. A total of 246 residents and immigrants living in the area at the age range of 4-60 years old were randomly selected to be tested for malaria by microscope, RDT, and nested-PCR techniques. The inclusion criterion for participants to be entered into the study was the absence of specific symptoms of malaria. Moreover, participants who have been taking antimalarials for the last month were excluded from the study. Results: The results indicated no positive cases of asymptomatic malaria among the participants tested by all methods. Conclusion: The results of this study have shown that, without concerns for asymptomatic parasitic patients, a malaria elimination program has been successfully implemented within the studies area. In addition, the findings emphasized the existence of a strong malaria surveillance system in this area.

Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase with Tetrazole Core.

INTRODUCTION: The attractive biological actions of the eicosatrienoic acids (EETs) and endocannabinoids (eCBs) are terminated by means of enzymatic hydrolysis via soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) enzymes. Simultaneous inhibition of both enzymes is considered a novel approach in the treatment of inflammatory and neuropathic pain. METHODS: In this study, a novel series of tetrazole derivatives as dual sEH/FAAH inhibitors were designed, synthesized, and biologically evaluated. Compounds 6c, 7d, and 8a, the most potent inhibitors against FAAH and sEH enzymes with acceptable IC50 values, significantly decreased carrageenan- induced paw edema 5h after carrageenan injection compared to the control group compound. In addition, compound 7d exhibited a significant reduction in pain scores compared to the control group. RESULTS: Docking studies showed that the presented dual inhibitors could bind to the essential residues in the catalytic sites of both enzymes. In silico prediction of several pharmacokinetic properties suggests that these dual inhibitors could potentially be orally active agents. CONCLUSION: These structures will be a valuable scaffold to develop soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.

Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex: Design, synthesis, radioligand binding assay, and pharmacological evaluation.

Agonists of Benzodiazepine (BZD) receptor are exhaustively used in the control of muscle spasms, seizure, anxiety, and insomnia. BZDs have some unwanted effects; therefore, the development of new BZD receptor agonists with better efficacy and fewer unwanted effects is one of the subjects of interest. In this study, based on the pharmacophore/receptor model of the BZD binding site of GABAA receptors, a series of new 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives (6a-f) were designed. Energy minima conformers of the designed compounds and diazepam were well matched in conformational analysis and showed proper interaction with the BZD-binding site of the GABAA receptor model (α1ß2ϒ2) in docking studies. The designed compounds were synthesized in acceptable yield and evaluated for their in vitro affinity to the benzodiazepine receptor of rat brains by radioligand receptor binding assay. The results demonstrated that the affinities of most of the novel compounds were even higher than diazepam. The novel compound 6a with the best affinity in radioligand receptor binding assay (Ki=0.44 nM and IC50= 0.73±0.17 nM) had considerable hypnotic activity and weak anticonvulsant and anxiolytic effects with no negative effect on memory in animal models. Flumazenil as a selective benzodiazepine receptor antagonist was able to prevent hypnotic and anticonvulsant effects of 6a indicating the role of BZD receptors in these effects.

A Comprehensive Review of Soluble Epoxide Hyådrolase Inhibitors Evaluating their Structure-Activity Relationship.

Soluble epoxide hydrolase is a class of α/ß-fold hydrolase enzymes that exist in numerous organs and tissues, including the liver, kidney, brain, and vasculature. This homodimer enzyme is responsible for degrading epoxyeicosatrienoic acids to the less active vicinal diols, dihydroxyeicosatrienoic acids by adding a molecule of water to an epoxide in the cytochrome P450 pathway. Soluble epoxide hydrolase was firstly assayed and characterized by Hammock and colleagues about 40 years ago. Upholding high epoxyeicosatrienoic acid blood levels by inhibiting soluble epoxide hydrolase has been proposed as a hopeful strategy to treat renal and cardiovascular diseases, inflammation, and pain. Therefore, developing novel soluble epoxide hydrolase inhibitors has been an attractive research topic for many years. Regarding this issue, some carbamates, heterocycles, amides, and ureas have been proposed; however, rapid metabolism, low solubility, high melting point, and weak pharmacokinetic characteristics are challenges posed to the researchers. In this review, we have focused on the role of the soluble epoxide hydrolase in the metabolic pathway of arachidonic acid, and categorized the most representative soluble epoxide hydrolase inhibitors into two main classes of synthetic and natural compounds. The structures have been evaluated and an exemplary structure-activity relationship has been provided for further development of potent inhibitors at the end. According to our findings, urea-based inhibitors were preferred to the amide-based scaffolds due to the better fitting into the active site. An aromatic linker is a suitable bridge to connect primary and secondary pharmacophores compared with aliphatic linkers.

Cerasome Versus Liposome: A Comparative Pharmacokinetic Analysis Following Intravenous Administration into Rats.

Background: Cerasomes, due to their external siloxane network, demonstrate markedly higher physicochemical stability and, therefore, easier handling and storage than liposomes. Objectives: The main objective of this study was to compare the pharmacokinetics (PK) of cerasome and liposome following intravenous administration. The PK of PEGylated and non-PEGylated cerasomes was also compared to see whether the presence of a hydrophilic siloxane network on the surface of cerasomes can play the role of polyethylene glycol (PEG) in increasing the blood circulation of these vesicles. Methods: Silver sulfide (Ag2S) quantum dots (Qds)-loaded PEGylated and non-PEGylated cerasomes and PEGylated liposomes were fabricated and thoroughly characterized in terms of particle size, polydispersity index, zeta potential, entrapment efficiency, and in vitro stability. For pharmacokinetic evaluation, the free Qds and the selected formulations were intravenously injected into rats, and blood samples were collected for up to 72 hours. Pharmacokinetic parameters were calculated by the non-compartmental method. Results: Both cerasomal and liposomal carriers significantly improved the PK of Qds. For example, the elimination half-life (t1/2) and the area under the plasma concentration-time curve from time 0 to time infinity (AUC0-∞) for the free Qds were 4.39 h and 8.01 µg/mL*h and for cerasomal and liposomal formulations were 28.82 versus 26.95 h and 73.25 versus 62.02 µg/mL*h, respectively. However, compared to each other, the plasma concentration-time profiles of PEGylated cerasomes and liposomes displayed similar patterns, and the statistical comparison of their pharmacokinetic parameters did not show any significant difference between the two types of carriers. For PEGylated cerasomes, t1/2 and AUC0-∞ values were respectively 1.6 and 3.3 times greater than the classic cerasome, indicating that despite the presence of a hydrophilic siloxane network, the incorporation of PEG is necessary to reduce the clearance of cerasomes. Conclusions: The comparable PK of PEGylated cerasomes and liposomes, along with the higher physicochemical stability of cerasomes, can be considered an important advantage for the clinical application of cerasomes. Additionally, the easy surface functionalizing ability of cerasomes confers a dual advantage over liposomes. The study findings also showed that the presence of a hydrophilic siloxane network on the surface of cerasomes alone is not enough to make them circulate long.

Host-Cell Surface Binding Targets in SARS-CoV-2 for Drug Design.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a major public health threat to all countries worldwide. SARS-CoV-2 interactions with its receptor are the first step in the invasion of the host cell. The coronavirus spike protein (S) is crucial in binding to receptors on host cells. Additionally, targeting the SARS-CoV-2 viral receptors is considered a therapeutic option in this regard. In this review of literature, we summarized five potential host cell receptors, as host-cell surface bindings, including angiotensin-converting enzyme 2 (ACE2), neuropilin 1 (NRP-1), dipeptidyl peptidase 4 (DPP4), glucose regulated protein-78 (GRP78), and cluster of differentiation 147 (CD147) related to the SARS-CoV-2 infection. Among these targets, ACE2 was recognized as the main SARS-CoV-2 receptor, expressed at a low/moderate level in the human respiratory system, which is also involved in SARS-CoV-2 entrance, so the virus may utilize other secondary receptors. Besides ACE2, CD147 was discovered as a novel SARS-CoV-2 receptor, CD147 appears to be an alternate receptor for SARSCoV- 2 infection. NRP-1, as a single-transmembrane glycoprotein, has been recently found to operate as an entrance factor and enhance SARS Coronavirus 2 (SARS-CoV-2) infection under in-vitro. DPP4, which was discovered as the first gene clustered with ACE2, may serve as a potential SARS-CoV-2 spike protein binding target. GRP78 could be recognized as a secondary receptor for SARS-CoV-2 because it is widely expressed at substantially greater levels, rather than ACE2, in bronchial epithelial cells and the respiratory mucosa. This review highlights recent literature on this topic.

Synthesis, Docking Study and Biological Evaluation of Amide-Based Soluble Epoxide Hydrolase Inhibitors with Novel Secondary Pharmacophore of Pyrimidin-2-ol.

Soluble epoxide hydrolase enzyme (sEH) is one of the most promising and emerging targets to develop drugs for multiple disease indications, including hypertension, diabetes, stroke, dyslipidemia, pain, etc. Most inhibitor scaffolds have a urea or amide moiety to mimic the active-site transition state. In this regard, we developed a series of amide sEH inhibitors with a pyrimidin-2-ol ring as a new secondary pharmacophore, which was subjected to in vitro evaluation. Compound 4w (4-chloro-N-{4-[6-(4-chlorophenyl)-2-hydroxypyrimidin-4-yl]phenyl}benzamide), which contains 4-chloro substituent in both terminal phenyl rings, exhibited the most inhibitory activity against sEH with an IC50 value of 1.2 nM. Molecular docking analysis of the synthesized compounds revealed that the greater number of hydrogen bonding interactions of the amide group as the primary pharmacophore with Asp-353, Tyr-383, and Tyr-466 as the key catalytic residue triad of the enzyme played a critical role and led to a more favorable binding affinity. Pharmacokinetic properties of the synthesized compounds were calculated in silico, and all ADMET indices fell within acceptable ranges. Altogether, the results of this work could provide useful information on 4,6-diphenylpyrimidin-2-olas sEH inhibitors which can be utilized in further development in this area.

Insights into the molecular mechanism of triazolopyrimidinone derivatives effects on the modulation of α1ß2γ2 subtype of GABAA receptor: An in silico approach.

Due to the importance of benzodiazepine drugs in clinical practice, such as the treatment of anxiety disorders, depression, and insomnia and the side effects of classical benzodiazepines, the study of new benzodiazepine agonists has received much attentions. In this work, we used in silico methods to explore the molecular mechanism of 1,2,4-triazolo [1,5-a] pyrimidinone derivatives in the modulation of α1ß2γ2 subtype of GABAA receptor. To this aim, molecular docking, molecular dynamics simulation (MD), post-MD analysis, binding free energy calculation, and prediction of ADME properties were performed. Results showed that all new compounds have a better binding affinity for the Benzodiazepine (BZD) site of the receptor than diazepam and compound 4c had the highest affinity among them. Moreover, a good agreement was observed between the calculated ΔGbinding and experimental IC50 values. Also, we noticed that residues in loop regions (particularly loop C and D-F in α1 and γ2 subunits, respectively) forming BZD binding site, take part in forming several H-bonds between the agonists and the receptor. Ser205, Thr207, Tyr160, and His102 of α1 subunit and Thr207 of γ2 subunit are mainly involved in forming H-bonds. Also, the orientation of agonists in the BZD binding site leads to π-π interactions with hydrophobic residues in loops A-F. Based on the DCCM analysis, the correlated motions in the γ2 subunit residues are greater than those of α1 subunit residues. Further, predicted ADME results indicated that all agonists meet the criteria. The triplicate MD simulation showed the reproducibility of the results and strengthened the study. Our results provide a comprehensive insight into the receptor-agonist interactions and clues for designing future BZD agonists.

Novel 2-(Diphenylmethylidene) Malonic Acid Derivatives as Anti-HIV Agents: Molecular Modeling, Synthesis and Biological Evaluation.

HIV, the virus that causes AIDS (acquired immunodeficiency syndrome), is one of the world's most severe health and development challenges. In this study, a novel series of 2-(diphenyl methylidene) malonic acid derivatives were designed as triple inhibitors of HIV reverse transcriptase, integrase, and protease. Docking models revealed that the target compounds have appropriate affinities to the active sites of the three HIV key enzymes. The synthesized malonic acid analogs were evaluated for their activities against the HIV virus (NL4-3) in HeLa cells cultures. Among them, compound 3 was the most potent anti-HIV agent with 55.20% inhibition at 10 µM and an EC50 of 8.4 µM. Interestingly, all the synthesized compounds do not show significant cytotoxicity at a concentration of 10 µM. As a result, these compounds may serve as worthy hits for the development of novel anti-HIV-agents.

Targeting EGFR Tyrosine Kinase: Design, Synthesis and Biological Evaluation of Novel Quinazolinone Derivatives.

Impaired cell cycle regulation and disturbance in signal transduction pathway are two major causes of a condition defined as cancer, one of the significant reasons for mortality worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been commonly used as anticancer agents, and the majority of this medications possess quinazoline moiety as a heteroaromatic core. In this study, two novel series of EGFR-TKIs containing quinazolinone core were designed and synthesized. Most compounds showed reasonable inhibitory activity against EGFR-TK compared to that of erlotinib, a reversible inhibitor of this enzyme. Compound 8b, 2-((2-chlorobenzyl)amino)-6-phenoxyquinazolin-4(1H)-one, with an IC50 value of 1.37 nM exhibited the highest potency. Molecular docking study of compound 8b showed that it had the same direction of erlotinib and formed proper hydrogen bonds and hydrophobic interactions with the important amino acid residues of the active site. Based on in-silico calculations of ADME properties, our novel compounds have the potential to be orally active agents.

Synthesis, Molecular Dynamics Simulation, and In-vitro Antitumor Activity of Quinazoline-2,4,6-triamine Derivatives as Novel EGFR Tyrosine Kinase Inhibitors.

Background: Developing a potent and safe scaffold is challenging in anti-cancer drug discovery. Objectives: The study focused on developing novel series of compounds based on the inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) as one of the most promising compounds in cancer therapy. Methods: In this study, a novel series of quinazoline-2,4,6-triamine derivatives were designed and synthesized through intramolecular C-H activation reaction of para-nitro aniline, trichloroacetonitrile, and isocyanides employing a one-pot reaction. Results: The in-vitro antitumor activities of the compounds which showed acceptable inhibitory effects were investigated against breast (MCF-7), lung (A-549), and colon (HT-29) cancer cell lines by employing MTT assay. All compounds had the most negligible cytotoxicity toward normal fibroblast human cell lines. Based on structural and thermodynamics analysis results, it was found that Met 769 is a key residue in interaction with all inhibitors through the formation of hydrogen bonds with high occupancies with the amine group on the quinazoline ring of inhibitors. Also, there was a good consistency between calculated ΔG binding and experimental IC50 values of compounds 10d, 10e, and erlotinib. Conclusions: Compound 10e had an extensive range of antitumor activity on three diverse cell lines comparable with erlotinib and doxorubicin reference drugs. Also, compound 10d showed selective cytotoxicity against cancerous lung cells (A-549). On the other side, computational studies confirmed that Met 769 is a crucial residue in interaction with all inhibitors.

Design, synthesis, and preliminary pharmacological evaluation of novel thiazolidinone derivatives as potential benzodiazepine agonists.

Thiazolidinones are well-known heterocycles that demonstrate promising biological effects such as anticonvulsant activity. Hybridization of these chemicals with scaffold, which has necessary pharmacophores for binding to the benzodiazepine receptors, can prompt a novel structure possessing extensive anticonvulsant effects. In this study, novel derivatives of thiazolidinone as new benzodiazepine agonists were designed, synthesized, and biologically evaluated. Compound 5h, 4-chloro-2-(2-fluorophenoxy)-N-(4-oxo-2-(p-tolyl)thiazolidin-3-yl)benzamide, exhibited considerable anticonvulsant activity, proper sedative-hypnotic effect, no memory impairment, and no muscle relaxant effect. The pharmacological effects of the designed compounds were antagonized by flumazenil, which confirmed the benzodiazepine receptors' involvement in their biological effects. Based on in silico calculations of ADME properties of our novel compounds, they could be active oral agents potentially. In this study, we designed novel structures by the hybridization of thiazolidinone moiety with scaffold which has necessary pharmacophores for binding to the benzodiazepine receptors. The results are very promising for developing new lead compounds as benzodiazepine agonists possess anticonvulsant effects.

Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis and biological evaluation.

Alzheimer's disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC50 value of 5.07 µM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer's agents (Figure 1(Fig. 1)).

Synthesis of 4,6-diphenylpyrimidin-2-ol derivatives as new benzodiazepine receptor ligands.

Benzodiazepines (BZDs) have been widely used in neurological disorders such as insomnia, anxiety, and epilepsy. The use of classical BZDs, e.g., diazepam, has been limited due to adverse effects such as interaction with alcohol, ataxia, amnesia, psychological and physical dependence, and tolerance. In the quest for new benzodiazepine agonists with more selectivity and low adverse effects, novel derivatives of 4,6-diphenylpyrimidin-2-ol were designed, synthesized, and evaluated. In this series, compound 2, 4-(2-(benzyloxy)phenyl)-6-(4-fluorophenyl)pyrimidin-2-ol, was the most potent analogue in radioligand binding assay with an IC50 value of 19 nM compared to zolpidem (IC50 = 48 nM), a nonbenzodiazepine central BZD receptor (CBR) agonist. Some compounds with a variety of affinities in radioligand receptor binding assay were selected for in vivo evaluations. Compound 3 (IC50 = 25 nM), which possessed chlorine instead of fluorine in position 4 of the phenyl ring, exhibited an excellent ED50 value in most in vivo tests. Proper sedative-hypnotic effects, potent anticonvulsant activity, appropriate antianxiety effect, and no memory impairment probably served compound 3, a desirable candidate as a benzodiazepine agonist. The pharmacological effects of compound 3 were antagonized by flumazenil, a selective BZD receptor antagonist, confirming the BZD receptors' involvement in the biological effects of the novel ligand.

Novel Derivatives of diphenyl-1,3,4-oxadiazol as Ligands of Benzodiazepine Receptors; Synthesize, Binding Assay and Pharmacological Evaluation.

Benzodiazepines (BZD) are among the main classes of tranquilizing drugs, bearing much less toxicity compared to other drugs acting on the CNS. Considering the pharmacophore model of BZD binding to GABA-A receptor, novel diphenyl 1,3,4-oxadiazole compounds as BZD ligands were designed. The compounds were synthesized and structurally confirmed using LCMS, IR and NMR techniques. We investigated the affinity of the compounds to BZD receptors using radioligand [3H]-flumazenil by in-vitro studies. In addition, sedative-hypnotic, anxiety, anticonvulsant, muscle relaxant, memory impairment, and motor coordination activities of the synthesized compounds were evaluated using in-vivo studies. Based on in-vitro studies, compounds 7i and 7j were the most potent with IC50 values of 1.54 and 1.66 nM respectively. In-vivo studies showed that compound 7i has the highest impact on increased sedation, muscle relaxation, and decreased anxiety and these observations were antagonized by flumazenil. Compounds 7e and 7i were the most potent anticonvulsant agents among synthesized compounds in both MES and PTZ induced seizure tests. All synthesized compounds significantly decreased latency to fall in the Rotarod test but none of them had a significant impact on the memory impairment test.

Novel amide derivatives of 3-phenylglutaric acid as potent soluble epoxide hydrolase inhibitors.

Soluble epoxide hydrolase (sEH) enzyme plays an important role in the metabolism of endogenous chemical mediators, epoxyeicosatrienoic acids, which are involved in the regulation of blood pressure and inflammation. According to the pharmacophoric model suggested for sEH inhibitors, some new amide-based derivatives of 3-phenylglutaric acid were designed, synthesized and biologically evaluated. Docking study illustrated that the amide group as a primary pharmacophore had a suitable distance from the three amino acids of Tyr383, Tyr466 and Asp335 for effective hydrogen binding. Most of the compounds showed moderate to high sEH inhibitory activities in in vitro test in comparison with 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid, as a potent urea-based sEH inhibitor. Compound 6o with phenethyl in R position exhibited the highest activity with IC50 value of 0.5 nM. In this study, some new amide-based derivatives of 3-phenylglutaric acid were designed, synthesized and biologically evaluated. Most of the synthesized compounds provided nanomolar range inhibition against sEH enzyme. The best observed IC50 value was 0.5 nM. Incorporating a carboxylic moiety into these structures by forming carboxylate salts would increase the solubility and improving physicochemical properties.

Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase.

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P2 ) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P1 ) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC50 value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.

Quinazoline-4(3H)-one derivatives as novel and potent inhibitors of soluble epoxide hydrolase: Design, synthesis and biological evaluation.

Inhibition of soluble epoxide hydrolase (sEH) is considered as a promising target to reduce blood pressure, improve insulin sensitivity, and decrease inflammation. In this study, a series of some novel quinazoline-4(3H)-one derivatives (3a-t) with varying steric and electronic properties was designed, synthesized and evaluated as sEH Inhibitors. Most of the synthesized compounds had similar inhibitory activity to the commercial reference inhibitor, 12-(3-adamantan-1-ylureido)dodecanoic acid, and amongst them, 4-chloro-N-(4-(4-oxo-3,4-dihydroquinazoline-2-yl)phenyl)benzamide (3g) was identified as the most active sEH inhibitor (IC50 = 0.5 nM), about 2-fold more potent compared to the reference inhibitor. The results of molecular modeling followed by biological studies indicate that a quinazolinone ring serves as a suitable scaffold to develop novel small molecule candidates to inhibit sEH and the nature of substituent on the amide moiety has a moderate effect on the activity.