Study of novel 1,4-dihydropyridine derivatives as prospective anti-inflammatory remedies: a randomised controlled trial

Background. Over the past decades, scientific community is motivated on finding new anti-inflammatory agents with a safe and high-effective profile to manage pathology.Objectives. A study of the anti-inflammatory action of novel compounds, 1,4-dihydropyridine derivatives, in a classical formalin-induced paw oedema test in white rats.Methods. Originally synthesised 1,4-dihydropyridine derivatives were preliminarily subjected to virtual screening using the SwissTargetPrediction toolkit. White laboratory rats (130 animals) were divided into a control (formalin oedema) and intact group, 4 comparison (meloxicam, sodium metamizole, sodium diclofenac and indomethacin) and 7 experiment groups by the number of 1,4-dihydropyridine derivatives studied. The samples anti-inflammatory efficacy was evaluated in acute formalin-induced paw oedema model simulated by right hind limb subplantar injection of 0.1 mL 2% formalin. The studied substances were administered intragastrically at 5 mg/kg 1.5 h prior to oedema induction. Oncometry was assessed quantitatively by limb circumference. Animals were managed in compliance with GOST 33044–2014 “Principles of Good Laboratory Practice” at all experiment steps. Experimental data were analysed statistically to describe quantitative variability with variance σ2, mean limb girth a and standard deviation σ. Data homogeneity and reliability were estimated by variation coefficient V and the Wilcoxon T(W) criterion.Results. As the most anti-inflammatory effective, partially hydrogenated mar-040 pyridines (ethyl 4-({[5-cyano-6-{[2-(diphenylamino)-2-oxoethyl]thio}-4-(2-furyl)-2-methyl-1,4-dihydropyridin-3-yl]carbonyl}amino) benzoate) were shown 33-fold superior to indomethacin, 26-fold — to sodium diclofenac, 25-fold — to meloxicam and 30-fold — to sodium metamizole; mar-037 pyridines (ethyl 4-[({[3-cyano-5-({[4-(ethoxycarbonyl)phenyl]amino}carbonyl)-4-(2-furyl)-6-methyl-1,4-dihydropyridin-2-yl]thio}acetyl)amino] benzoate) — 17–23-fold superior vs. reference drugs. We also show that mаr-014 (ethyl 4-({[5-cyano-6-({2-[(3,5-dichlorophenyl) amino]-2-oxoethyl}thio)-4-(2-furyl)-2-methyl-1,4-dihydropyridin-3-yl]carbonyl}amino)benzoate) and mar033 (ethyl 2-[({[3-cyano-5-({[4-(ethoxycarbonyl)phenyl]amino}carbonyl)-4-(2-furyl)-6-methyl-1,4-dihydropyridin-2-yl]thio}acetyl)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate) compounds are 2.7-fold more effective vs. reference drugs.Conclusion. The synthesised 1,4-dihydropyridine compounds reveal high efficacy in experimental assays. Selected novel 1,4-dihydropyridine derivatives exhibit a marked anti-inflammatory activity and offer value in future preclinical trials

Peculiarities of pharmacological activity of tetrahydropyridone and hexahydroquinoline derivatives in experiment

Due to widespread inflammatory processes, often accompanied by pain and fever syndromes, NSAIDs are now the most prescribed drug group in the world. NSAIDs are characterized by taking a leading position in the number and severity of adverse actions. In recent decades, the efforts of scientists have been aimed at seaching for adequate ways to increase the safety profile of NSAID

(2E)-2-(2,4-Dichloro­phenyl­sulfon­yl)-3-(4-methyl­anilino)-3-(methyl­sulfan­yl)acrylonitrile

The title compound, C17H14Cl2N2O2S2, and the 3-methoxy­anilino analogue reported in the preceding paper have been used as starting materials to develop benzothia­zine derivatives with anti­malarial activity. The mol­ecule displays an E (trans) configuration about the central double bond. Due to conjugation in the C=C—C N group, the putative single bond shows a significant shortening [1.418 (3) Å]. The mol­ecule has a six-membered ring involving an intra­molecular N—H⋯O(sulfon­yl) bond, which is an example of resonance-assisted hydrogen bonding. In the crystal structure, bonds of the C—H⋯O(sulfon­yl) and C—H⋯N(cyano) types form double layers of mol­ecules parallel to (01). Within these layers there are π–π inter­actions between benzene rings of pairs of centrosymmetrically related mol­ecules, with distances of 3.7969 (12) Å between centroids. C—H⋯π interactions are also present

Empirical determination of the degree of analgesic activity of some new 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines based on a complex criterion

It is revelant to solve the problem of anesthesia based on the research of new highly effective and safe medicines. Among modern studies, the preparation of heterocyclic compounds starting from cyanothioacetamide with analgesic and anti-inflammatory activities is of considerable interes

New hybrid molecules based on sulfur-containing nicotinonitriles: synthesis, analgesic activity in acetic acid-induced writhing test, and molecular docking studies

New hybrid molecules bearing furyl and 1,4-dihydronicotinonitrile (or 1,4,5,6-tetrahydronicotinonitrile) fragments have been prepared. The analgesic activity was studied in vivo (rats) in acetic acidinduced writhing test. Some compounds showed activity exceeding that of the reference compound (metamizole

Synthesis and analgesic activity of new heterocyclic cyanothioacetamide derivatives

The reaction of cyanothioacetamide with aromatic aldehydes and 1,3-dicarbonyl compounds followed by aminomethylation or S-alkylation gave a series of heterocyclic derivatives with a 1,2,3,4-tetrahydropyridine or 1,4,5,6,7,8-hexahydroquinoline fragment. The resulting compounds were tested for analgesic activity in vivo. Some of the prepared compounds showed an antinociceptive effect superior to that of ketorolac in dynamic

Study of anti-inflammatory and antinociceptive properties of new derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines

Background. α-сyanothioacetamide derivatives are promising targets for the search for effective and safe antinociceptive agents with antipyretic and antiexudative activity. The aim. To conduct in vivo experimental study of anti-inflammatory and analgesic effects of new thienopyridines and 1,4-dihydropyridines derivatives. Materials and methods. The synthesized cyanothioacetamide derivatives were subjected to virtual bioscreening using Swiss Target Prediction online service. 140  laboratory rats were randomly distributed into intact and control (dextran edema) groups, reference groups (acetylsalicylic acid and  nimesulide) and ten experimental groups for the investigated derivatives of thieno[2,3-b]pyridine and 1,4-dihydropyridine. The anti-inflammatory activity of the compounds at a dose of 5 mg/kg was evaluated by modeling acute dextran edema of rat paw. Determination of analgesic activity was carried out in the hotplate analgesic assay on 130 rats in comparison with sodium metamizole. Results. 1,4-dihydropyridines AZ331 and AZ420, as well as thienopyridine derivative AZ023 were determined to have strong anti-inflammatory activity (2.5 times more effective than nimesulide and 2.2 times more effective than acetylsalicylic acid). Compounds AZ023, AZ331 and AZ383 showed pronounced analgesic activity. The time of stay on the heated plate for rats of experimental groups that were fed with AZ331 and AZ383 for prophylactic purpose was respectively 9.56 and 9.93 times more than the same index in the reference group. The animals receiving AZ023 were characterized by an increase in the latent reaction time up to 241.2 seconds, which is 14.53 times higher than that in the rats received sodium metamizole. Conclusion. New thienopyridine and 1,4-dihydropyridine derivatives with high antiinflammatory and analgesic activity were synthesized and studied; they were recognized as promising targets for further preclinical studies

Novel 1,4-Dihydropyridine Derivatives as Potential Agents with Analgesic Activity IN Orofacial Trigeminal Pain Test: Experimental Preclinical Randomized Trial

Background. In the majority of cases, contemporary pharmacological correction mainly focuses on the most effective analgesia. Therefore, the search for and research into new analgesic drugs are a priority in modern pharmacology.Objective — to establish the level of analgesic activity in eight novel heterocyclic compounds of 1,4-dihydropyridine derivatives synthesized in a classic test of orofacial trigeminal pain in animal experiments.Methods. An experimental preclinical randomized trial of the analgesic activity in 1,4-dihydropyridine derivatives was carried out. The experiment was conducted on 100 white male outbred rats in the laboratory of the Fundamental and Clinical Pharmacology Department, St. Luke Lugansk State Medical University, Lugansk People’s Republic. Novel 1,4-dihydropyridine derivatives were preliminarily investigated in a virtual biological screening by means of Swiss Target Prediction tool (Swiss Institute of Bioinformatics, Switzerland). The laboratory animals were divided into a control group (rats were exposed to acute pain syndrome by injecting 0.1 ml of 5% formalin solution into the vibrissae area without pharmacological correction), a comparison group (rats which received metamizole sodium (OOO Farmstandard) at a dose of 7 mg/kg 1.5 hour prior to acute pain syndrome modeling in the vibrissae area), and eight experimental groups (1.5 hours before formalin administration, novel 1,4-dihydropyridine derivatives under study at a dose of 5 mg/ kg were intragastrically injected). 10, 15 and 20 minutes after simulating acute pain, the number of scratching movements of the forelegs around orofacial region per minute was counted. Statistical processing of the results involved methods of mathematical statistics for quantitative variability and was carried out using Statistica 12.5 (IBM, USA).Results. Animals treated with 1,4-dihydropyridine derivatives d02-133 and d02-172 under the experimental conditions showed a significant (13–21 times) decrease in scratching movements frequency by the 10th minute of observation in comparison with the control group. By 15th minute, the analgesic activity of the cyanothioacetamide derivatives increased 14 and 11 times as compared to these indicators of the reference group. After 20 minutes, the analgesic activity of these compounds in terms of inhibiting nociceptive impulses, as compared to the control group, was also high, as the number of scratching movements in the vibrissae area in animals of these experimental groups was 8–9 times lower than in control group. The orofacial trigeminal pain test detected the most exhibited analgesic activity in novel cyanothioacetamide derivatives d02-139, d02-133, and d02-172, which appeared to be higher than that of metamizole sodium.Conclusion. It was found that novel original derivatives of 1,4-dihydropyridine showed a high degree of analgesic activity

Изучение адаптогенной активности производных тетрагидропиридо[2,1-b][1,3,5]тиадиазина

Introduction. In the modern world people are exposed to the influence of adverse psychological and physical factors, escalating in intensity. The search for new pharmacodynamic effects of [1,3,5]-thiadiazine derivatives designated by significant biological activity of these compounds is an essential issue.Aim. To research adaptogenic activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives using a modified Porsolt Forced Swim Test.Materials and methods. Four substances from the group of 3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6Hpyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles were selected for the research. Rats were divided into a control group, 5 reference groups (amitriptyline, caffeine, thiotriazolin, thiocetam, ginseng) and 4 experimental groups according to the number of the studied original tetrahydropyrido[2,1-b][1,3,5] thiadiazine derivatives.Results. Intragastric injection of substance 2 for 5 days in the modified forced swim test (forced swimming with freight) increased work capacity and endurance of the rats by 103.42% as opposed to the initial results. The detected adaptogenic activity of this tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivative six times exceeds adaptogenic activity of ginseng and seven times that of amitriptyline. The rats in the control group were active for a bit longer time. Ginseng raised the time of activity by 17% at day 5. Caffeine essentially reduced work capacity and endurance. Amitriptyline showed adaptogenic activity at day 3 of the research (increase by 10.4%). Thiotriazolin also showed adaptogenic activity on day 3 of the research (increase by 30.17%). Thiocetam increased the time of activity by 78.55%. Substance 4 had adaptogenic activity too; it increased the time of activity in aversive conditions by 58.25%, which three times exceeds this parameter for ginseng and four times for amitriptyline. Введение. Статья посвящена изучению новых биологически активных соединений на основе производных тетрагидропиридо[2,1-b][1,3,5]тиадиазина. Исследуемые образцы обладают выраженным аналептическим и антидепрессантным эффектом.Цель исследования – оценка адаптогенной активности производных тетрагидропиридо[2,1-b][1,3,5] тиадиазина с помощью модификации теста поведенческого отчаяния (беспомощности) по Порсольту.Материалы и методы. Для исследования были отобраны четыре оригинальных соединения, проявившие высокую активность в предыдущих тестах. В качестве препаратов сравнения выступали кофеин-бензоат натрия, женьшень, тиотриазолин, тиоцетам, амитриптилин.Результаты. Внутрижелудочное введение соединения 2 на протяжении 5 сут в модифицированном тесте поведенческого отчаяния по Порсольту (вынужденное плавание с грузом) вызвало увеличение работоспособности и выносливости крыс на 103,42% в сравнении с первоначальными показателями. Выявленная адаптогенная активность этого производного тетрагидропиридо[2,1-b][1,3,5]тиадиазина в 6 раз превосходит таковую у женьшеня и семикратно у амитриптилина. Соединение 4 также обладало адаптогенной активностью, увеличивая время сохранения активности в аверсивной среде на 58,25%, что в 3 раза превышало показатели в группе сравнения с женьшенем и в 4 раза – с амитриптилином.