Evaluation of N-benzoylthiourea derivatives as popssible analgesic agents by predicting their hysicochemical and pharmacokinetic properties, toxicity, and analgesic activity

This study aimed to predict the physicochemical properties, pharmacokinetic properties (ADME), toxicity, and analgesic activity of 30 compounds of N-benzoylthiourea derivatives that are potential analgesic drugs. One of the mechanisms of action of N-benzoylthiourea derivatives is the inhibition of the cyclooxygenase-2 (COX-2) isoenzyme. An in silico test was performed by docking a compound that would predict its activity with the target COX-2 isoenzyme, PDB ID: 1PXX, using the MVD (Molegro Virtual Docker) program. The result of the docking was a form of energy bond indicated by the value of the rerank score (RS), where compounds that had lower RS values were predicted to have a higher activity. The pkCSM and Protox online tools were used to predict various physicochemical properties. Based on the RS values, the N-benzoylthiourea derivatives can be predicted to have lower analgesic activity than diclofenac, the reference ligand. Three of the N-benzoylthiourea derivatives—N-(2,4-bis-trifluoromethyl)-benzoylthiourea, N-(3,5-bis-trifluoromethyl)benzoylthiourea, and N-(3-trifluoromethoxy)-benzoylthiourea—had RS values of -90.82, -94.73, and -92.76, respectively, suggesting that these compounds were predicted to have analgesic activity relatively similar to diclofenac (RS value = -95.16). Furthermore, the majority of the N-benzoylthiourea derivatives were predicted to have good pharmacokinetic properties (ADME), and cause relatively low toxicity.

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In Silico Analysis of Antiviral Activity and Pharmacokinetic Prediction of Brazilein Sappan Wood (Caesalpinia sappan L.) Against SARS-CoV-2 Spike Glycoproteins

Indonesian Journal of Medical Laboratory Science and Technology ◽

10.33086/ijmlst.v3i1.1854 ◽

2021 ◽

Vol 3 (1) ◽

pp. 26-37

Author(s):

Dwi Krihariyani ◽

Edy Haryanto ◽

Retno Sasongkowati

Keyword(s):

Vitamin C ◽

Antiviral Activity ◽

Bond Energy ◽

In Silico ◽

In Silico Analysis ◽

Data Bank ◽

Online Tool ◽

Molegro Virtual Docker ◽

Pharmacokinetic Properties ◽

Low Toxicity

Brazilein is one of the secondary sappan wood metabolites which can be used empirically as an antivirus. The SARS-CoV-2 spike (S) glycoproteins play significant roles in attaching and entering the virus into the host cell. This study aims to predict the antiviral activity and pharmacokinetic properties of brazilein of the sappan wood against the in-silico SARS-CoV-2 S glycoproteins with vitamin C as the reference compound. Molegro Virtual Docker 5.5 was used to predict antiviral activity by docking process. SARS-CoV-2 S glycoprotein with NAG ligand available in Protein Data Bank (PDB) (PDB ID: 7C01) was the receptor used. The pkCSM online tool was used to predict the pharmacokinetic properties and toxicity of brazilein. Data were analyzed on the target receptors by comparing the docking bond energies between NAG, brazilein, and vitamin C. The smaller the ligands’ bond energy to the target receptor, the more stable the bonds are. The bond energy of NAG, brazilein, and vitamin C was -59.2864 kcal/mol, -65.8911 kcal/mol, and -53.9093 kcal/mol, respectively. These results suggested that brazilein has a greater capacity as an antivirus compared to NAG and vitamin C. In silico test using the pkCSM online tool demonstrated that brazilein had strong pharmacokinetic properties and relatively low toxicity.

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IN SILICO DESIGN AND MOLECULAR DOCKING STUDIES OF SOME 1, 2-BENZISOXAZOLE DERIVATIVES FOR THEIR ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY

International Journal of Current Pharmaceutical Research ◽

10.22159/ijcpr.2017.v9i3.18886 ◽

2017 ◽

Vol 9 (3) ◽

pp. 133

Author(s):

Sarath Sasi Kumar ◽

Anjali T

Keyword(s):

Molecular Docking ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Analgesic Activity ◽

In Silico ◽

Docking Studies ◽

Inflammatory Activity ◽

Nicotinic Acetylcholine ◽

Cox 2 ◽

Anti Inflammatory

Objective: In silico design and molecular docking of 1,2-benzisoxazole derivatives for their analgesic and anti-inflammatory activity using computational methods.Methods: In silico molecular properties of 1,2-benzisoxazole derivatives were predicted using various software’s such as Chemsketch, Molinspiration, PASS and Schrodinger to select compounds having optimum drug-likeness, molecular descriptors resembling those of standard drugs and not violating the ‘Lipinski rule of 5’. Molecular docking was performed on active site of nicotinic acetylcholine receptor (PDB: 2KSR) for analgesic activity and COX-2 (PDB: 6COX) for anti-inflammatory activity using Schrodinger under maestro molecular modelling environment.Results: From the results of molecular docking studies of 1,2-benzisoxazole derivatives, all the compounds showed good binding interactions with Nicotinic acetylcholine receptor and COX-2. Compounds 4a and 4c showed highest binding scores (-7.46 and-7.21 respectively) with nicotinic acetylcholine receptor and exhibited maximum analgesic activity. Compound 4a showed highest binding score (-7.8) with COX-2 and exhibited maximum anti-inflammatory activity.Conclusion: All the derivatives of 1,2-benzisoxazole showed good analgesic and anti-inflammatory activity as predicted using molecular docking on respective receptors.

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Evaluation of analgesic activity of levofloxacin in adult albino rats

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20205544 ◽

2020 ◽

Vol 10 (1) ◽

pp. 85

Author(s):

Prasanna Kumari S. ◽

Latha K. ◽

Meeradevi A.

Keyword(s):

Analgesic Activity ◽

Bacterial Infections ◽

Albino Rats ◽

Tail Flick ◽

Albino Rat ◽

Group Iii ◽

Group I ◽

Analgesic Agents ◽

Active Isomer ◽

Animal House

Background: Levofloxacin is a fluorinated quinolone antimicrobial used in the treatment of various bacterial infections and was active against both gram positive and gram negative bacteria. Levofloxacin is an optically active isomer of ofloxacin. Apart from its antibacterial action, it also exhibit antinociceptive properties. This study was conducted with the aim to evaluate the analgesic activity of Levofloxacin in albino rat in comparison with aspirin.Methods: Thirty adult albino rats weighing 150-250 gm were obtained from central animal house. The animals were divided into five groups of six animals each. Group I served as control received normal feed and water. Group II served as standard received tablet aspirin 100 mg/kg (oral) and Group III, IV, V served as test T1, T2, T3 and received tablet levofloxacin 10 mg/kg, 20 mg/kg and 40 mg/kg (oral), respectively. The analgesic effect of levofloxacin was evaluated using Eddy’s hot plate and tail flick methods and compared with standard analgesic aspirin. The values obtained were expressed as mean±SD. Statistical analysis of difference between groups were carried out using one-way analysis of variance (ANOVA). Probability p<0.05 was taken as the level of statistical significance.Results: Levofloxacin at 40 mg/kg showed statistically (p<0.05) elevation in pain threshold and a higher antinociceptive activity in comparison to control and standard groups.Conclusions: In the present study, levofloxacin has showed promising results as an analgesic when compared to the control and standard groups. It may be a lead compound for identifying newer adjuvant analgesic agents.

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Evaluation of pharmacokinetic properties of isobornylphenols in silico

The Siberian Journal of Clinical and Experimental Medicine ◽

10.29001/2073-8552-2020-35-4-79-86 ◽

2020 ◽

Vol 35 (4) ◽

pp. 79-86

Author(s):

O. I. Ostrikova ◽

O. E. Vaizova ◽

O. I. Aliev ◽

E. V. Buravlev ◽

I. Yu. Chukicheva ◽

...

Keyword(s):

Toxicity Assessment ◽

Pharmacokinetic Parameters ◽

Structure Property ◽

Solubility In Water ◽

Virtual Tools ◽

Internet Resources ◽

P Glycoprotein ◽

Pharmacokinetic Properties ◽

Low Toxicity ◽

Low Solubility

Introduction. The potential of a new compound in the ongoing drugs discovery process is initially explored using virtual instruments, where its activity is predicted based on its molecular structure.Aim. This study aimed to evaluate the pharmacokinetic parameters and possible toxicity of isobornyl compounds based on virtual tools.Material and Methods. Several free Internet resources were used to assess the absorption, distribution, metabolism, excretion (ADME), and toxicity (T) of 2,6-diisobornyl-4-methylphenol (1, Dibornol), 2-hydroxy-3-isobornyl-5-methylbenzaldehyde (2), and 2-((di-n-butylamino) methyl)-6-isobornyl-4-methylphenol (3). Pharmacokinetic properties were calculated on ADMETlab platform. Toxicity and physical properties were evaluated using TEST software based on the structure-property quantification models of organic substances according to structure–property principle. Web server ProTox_II was used for acute toxicity assessment.Results. Plasma protein binding degrees were 76,9% for (1), 85,9% for (2), and 91,8% for (3). All three compounds were capable of penetrating the blood-brain barrier. Dibornol was identified neither as a substrate nor as an inhibitor of P-glycoprotein unlike (2) and (3). The half-life of all compounds was short (about 2 hours); the clearance was slow (about 2 mL/min*kg). The study showed that (2) and (3) potentially exert the toxic effects during the developmental stage of the organism, while ADMETlab showed potential cardio- and hepatotoxicity for (2) and (3), respectively. All compounds had extremely low solubility in water, which affected the assessments of other indicators by TEST software. The ProTox_II server showed the extremely low toxicity LD50 for all compounds (toxicity class 5).

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Synthesis of Novel Diclofenac Hydrazones: Molecular Docking, Anti-Inflammatory, Analgesic, and Ulcerogenic Activity

Journal of Chemistry ◽

10.1155/2020/4916726 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Nawaf A. Alsaif ◽

Mashooq A. Bhat ◽

Mohamed A. Al-Omar ◽

Hanaa M. Al-Tuwajiri ◽

Ahmed M. Naglah ◽

...

Keyword(s):

Molecular Docking ◽

Analgesic Activity ◽

Binding Affinities ◽

Standard Drug ◽

Reference Drug ◽

Ulcerogenic Activity ◽

Cox 2 ◽

Anti Inflammatory ◽

Sparing Effect ◽

Cox 1

This study was aimed to design novel diclofenac hydrazones having anti-inflammatory and analgesic activity with gastric sparing effect. A new series of 2-[2-(2,6-dichloroanilino)phenyl]-N’-[(substituted phenyl) methylidene] acetohydrazide derivatives (1−14) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activity. The compounds were identified and confirmed by elemental analysis and spectral data. During anti-inflammatory activity by carrageenan-induced paw edema method, compounds (2, 3, 7, 8, 11, and 13) were found to be most promising. Compounds 3, 8, and 13 have been found to have significant analgesic activity compared to the reference drug diclofenac in analgesic activity by both the hot plate method and acetic acid-induced writhing method. The compounds which presented highly significant anti-inflammatory and analgesic activity were further tested for their ulcerogenic activity. Compounds 3 and 8 showed maximum ulcerogenic reduction activities. Compound 8 was found to have LD50 of 168 mg/kg. Compound 8 with 3,5-dimethoxy-4-hydroxyphenyl substitution was found to be the most promising anti-inflammatory and analgesic agent with gastric sparing activity. Molecular docking of compounds was performed for COX−1/COX−2 binding site. Lead compound 8 showed better binding affinities of −9.4 kJ/mol with both COX-1 and COX-2 as compared to the standard drug, diclofenac with binding affinities of −6.6 kJ/mol and −8.1 kJ/mol for COX−1 and COX−2, respectively.

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Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽

10.1126/science.abb4489 ◽

2020 ◽

Vol 368 (6497) ◽

pp. 1331-1335 ◽

Cited By ~ 195

Author(s):

Wenhao Dai ◽

Bing Zhang ◽

Xia-Ming Jiang ◽

Haixia Su ◽

Jian Li ◽

...

Keyword(s):

Antiviral Drug ◽

X Ray ◽

Drug Candidates ◽

Lead Compounds ◽

Main Protease ◽

Pharmacokinetic Properties ◽

Key Enzyme ◽

Low Toxicity ◽

Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

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Synthesis of new ibuprofen hybrid conjugates as potential anti-inflammatory and analgesic agents

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0109 ◽

2020 ◽

Vol 12 (15) ◽

pp. 1369-1386

Author(s):

Siva S Panda ◽

Adel S Girgis ◽

Hitesh H Honkanadavar ◽

Riham F George ◽

Aladdin M Srour

Keyword(s):

Writhing Test ◽

Rat Paw Edema ◽

Analgesic Agents ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory ◽

Rat Paw ◽

Inhibition Studies

Background: A new set of hybrid conjugates derived from 2-(4-isobutylphenyl)propanoic acid (ibuprofen) is synthesized to overcome the drawbacks of the current non-steroidal anti-inflammatory drugs. Results & methodology: Synthesized conjugates were screened for their anti-inflammatory, analgesic and ulcerogenic properties. Few conjugates were found to have significant anti-inflammatory properties in the carrageenan-induced rat paw edema test, while a fair number of conjugates showed promising peripheral analgesic activity in the acetic acid-induced writhing test as well as central analgesic properties in the in vivo hot plate technique. The newly synthesized conjugates did not display any ulcerogenic liability. Conclusion: In vitro, COX-1 and COX-2 enzyme inhibition studies raveled compound 7e is more selective toward COX-2 compared with ibuprofen.

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The use of analgesic drugs by South African veterinarians : continuing education

Journal of the South African Veterinary Association ◽

10.4102/jsava.v72i1.613 ◽

2001 ◽

Vol 72 (1) ◽

Cited By ~ 33

Author(s):

K.E. Joubert

Keyword(s):

Chronic Pain ◽

Continuing Education ◽

South African ◽

Specific Drug ◽

Analgesic Drugs ◽

Flunixin Meglumine ◽

Post Operative Pain ◽

Analgesic Agents ◽

Anti Inflammatory ◽

Balanced Anaesthesia

According to a survey, non-steroidal anti-inflammatory agents were the most popular analgesic used in South Africa for management of peri-operative pain, acute post-operative pain and chronic pain. The most popular non-steroidal anti-inflammatory agents are flunixin meglumine and phenylbutazone. The most popular opioid type drug is buprenorphine, followed by morphine. In the peri-operative setting, analgesic agents were not actively administered to 86.3 % of cats and 80.7 % of dogs. Analgesic premedications were frequently administered, e.g. xylazine or ketamine, but no specific drug was administered for post-operative pain. Veterinarians need to critically review their anaesthetic and analgesic practices in order to achieve balanced anaesthesia.

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Druggability profile of stilbene-derived PPAR agonists: determination of physicochemical properties and PAMPA study

MedChemComm ◽

10.1039/c9md00286c ◽

2019 ◽

Vol 10 (11) ◽

pp. 1892-1899

Author(s):

Pasquale Linciano ◽

Barbara De Filippis ◽

Alessandra Ammazzalorso ◽

Pasquale Amoia ◽

Felisa Cilurzo ◽

...

Keyword(s):

Physicochemical Properties ◽

Neurodegenerative Disorders ◽

Pharmacokinetic Properties ◽

Prevention And Treatment ◽

Ppar Agonists ◽

Therapeutic Opportunity

PPAR agonists represent a new therapeutic opportunity for the prevention and treatment of neurodegenerative disorders, but their pharmacological success depends on favourable pharmacokinetic properties and capability to cross the BBB.

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Synthesis of Novel Benzodifuranyl; 1,3,5-Triazines; 1,3,5-Oxadiazepines; and Thiazolopyrimidines Derived from Visnaginone and Khellinone as Anti-Inflammatory and Analgesic Agents

Molecules ◽

10.3390/molecules25010220 ◽

2020 ◽

Vol 25 (1) ◽

pp. 220 ◽

Cited By ~ 6

Author(s):

Ameen Ali Abu-Hashem ◽

Sami A Al-Hussain ◽

Magdi E. A. Zaki

Keyword(s):

Sodium Ethoxide ◽

Standard Drug ◽

Chemical Structures ◽

Cyclooxygenase 1 ◽

Analgesic Agents ◽

Cox 2 ◽

Anti Inflammatory ◽

New Compounds ◽

Cox 2 Inhibitors ◽

Cox 1

Novel (4-methoxy or 4,8-dimethoxy)-3-methyl-N-(6-oxo-2-thioxo-1,2,3, 6-tetrahydro- pyrimidin-4-yl) benzo [1,2-b: 5, 4-b’] difuran-2-carboxamide (5a–b) has been synthesized by the reaction of visnagenone–ethylacetate (2a) or khellinone–ethylacetate (2b) with 6-aminothiouracil in dimethylformamide or refluxing of benzofuran-oxy-N-(2-thioxopyrimidine) acetamide (4a–b) in sodium ethoxide to give the same products (5a,b) in good yields. Thus, compounds 5a–b are used as an initiative to prepare many new heterocyclic compounds such as 2-(4-(3-methylbenzodifuran- 2-carbox-amido) pyrimidine) acetic acid (6a–b), N-(thiazolo[3, 2-a]pyrimidine)-3-methylbenzo- difuran-2-carboxamide (7a–b), N-(2-thioxopyrimidine)-methylbenzodifuran-2-carbimidoylchloride (8a–b), N-(2-(methyl-thio) pyrimidine)-3-methylbenzodifuran-2-carbimidoylchloride (9a–b), N-(2, 6 -di(piperazine or morpholine)pyrimidine)-1-(3-methylbenzodifuran)-1-(piperazine or morpholine) methanimine(10a–d), 8-(methylbenzodifuran)-thiazolopyrimido[1,6-a][1,3,5]triazine-3,5-dione (11a –b), 8-(3-methyl benzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-trione (12a–b), and 2,10 -di(sub-benzylidene)-8-(3-methylbenzodifuran)-thiazolopyrimido[6,1-d][1,3,5]oxadiazepine-3,5,11- trione (13a–f). All new chemical structures were illustrated on the basis of elemental and spectral analysis (IR, NMR, and MS). The new compounds were screened as cyclooxygenase-1/ cyclooxygenase-2 (COX-1/COX-2) inhibitors and had analgesic and anti-inflammatory activities. The compounds 10a–d and 13a–f had the highest inhibitory activity on COX-2 selectivity, with indices of 99–90, analgesic activity of 51–42% protection, and anti-inflammatory activity of 68%–59%. The inhibition of edema for the same compounds, 10a–d and 13a–f, was compared with sodium diclofenac as a standard drug.

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