Quinoline based furanones and their nitrogen analogues: Docking, synthesis and biological evaluation.

A small library of twenty-four quinoline based butenolides also known as furanones and their nitrogen analogues was prepared by using two different aroylpropionic acids, viz. 3-(2-naphthoyl)propionic acid (3) and 3-(biphenyl-4-yl)propionic acid (4), as starting materials. The 3-aroylpropionic acids were reacted with different 6-substituted-2-chloroquinolin-3-carbaldehydes (2a-d) to obtain the corresponding furan-2(3H)-ones (5a-h). The purified and characterized furanones were then converted into their corresponding 2(3H)-pyrrolones (6a-h) and N-benzyl-pyrrol-2(3H)-ones (7a-h). The antimicrobial activities of the title compounds were evaluated against two strains of each Gram +ve (Staphylococcus aureus and Bacillus subtilis), Gram -ve bacteria (Escherichia coli and Pseudomonas aeruginosa) and against fungal strains of Aspergillus niger and Aspergillus flavus. In vivo anti-inflammatory potential of the title compounds was investigated by standard method. Majority of the compounds showed significant antibacterial activity against both the Gram +ve strains. Eight most potent anti-inflammatory compounds (5b, 5d, 5h, 6b, 7b, 7d, 7f, 7h) which exhibited >53% inhibition in edema, were also screened for their in vivo analgesic activity. All the tested compounds were found to have significant reduction in ulcerogenic action but only three compounds (5d, 5h and 7h) showed comparable analgesic activity to standard drug, diclofenac. The results were also validated using in silico approach and maximum mol doc score was obtained for compounds 7a-h. On comparing the in vivo and in silico anti-inflammatory results of synthesized compounds, N-benzyl pyrrolones (7a-h) emerged as the potent anti-inflammatory agents. It was also observed that compounds that possess electron withdrawing group such as -Cl or NO2 are more biologically active.

Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents.

Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ⩾80%. In addition, pyrazolylthiazole carboxylic acids (2a-2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25µg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25µg/mL).

Dual evaluation of some novel 2-amino-substituted coumarinylthiazoles as anti-inflammatory-antimicrobial agents and their docking studies with COX-1/COX-2 active sites.

Synthesis of total eighteen 2-amino-substituted 4-coumarinylthiazoles including sixteen new compounds (3a-o and 5b) bearing the benzenesulfonamide moiety is described in the present report. All the synthesized target compounds were examined for their in vivo anti-inflammatory (AI) activity and in vitro antimicrobial activity. Results revealed that six compounds (3 d, 3 f, 3 g, 3 h, 3 j and 3 n) exhibited pronounced anti-inflammatory activity comparable to the standard drug indomethacin. AI results were further confirmed by the docking studies of the most active (3n) and the least active compound (3a) with COX-1 and COX-2 active sites. In addition, most of the compounds exhibited moderate antimicrobial activity against Gram-positive bacteria as well as fungal yeast, S. cervisiae. Comparison between 3 and 5 indicated that incorporation of additional substituted pyrazole nucleus into the scaffold significantly enhanced AI activity.

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors.

Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a-2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-ß-diketones (5a-5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H2S gas in the presence of triethylamine. All the synthesized compounds (2a-2i and 3a-3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3-4h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data.

Anticonvulsant activity of alcoholic extract of bark of Pinus roxburghii Sarg.

OBJECTIVE: To study the anticonvulsant activity of alcoholic extract of bark of Pinus roxburghii Sarg. (AEPR) used in Indian traditional medicine system in treating convulsion. METHODS: Anticonvulsant activity was evaluated by maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in Wistar albino rats. In the MES model, 150 mA current for 0.2 s was given through ear electrodes to induce convulsions in rats. The duration of tonic extension of hind limb was used as the end point, namely, prevention or decrease in the duration of hind limb extension was considered as a protective action. In the PTZ model, the anticonvulsant property of AEPR was assessed by its ability to delay the onset of myoclonic spasm and clonic convulsions produced by intraperitoneal administration of PTZ. RESULTS: In the MES-induced seizure model, AEPR in doses of 300 and 500 mg/kg body weight reduced all the phases of convulsion significantly (P<0.01). Standard drug phenytoin at a dose of 25 mg/kg significantly reduced flexion phase (P<0.01) and abolished all phases of convulsion. In the PTZ-induced seizure model, the administration of the extract at doses of 300 and 500 mg/kg 30 min prior to injection of PTZ significantly delayed the onset of clonic seizure (P<0.01). AEPR at the dose of 100 mg/kg body weight could not exert any significant protective effect on PTZ-induced convulsions. Standard drug diazepam at a dose of 4 mg/kg showed much delayed onset of clonic seizure. CONCLUSION: The study suggests that AEPR would be effective against generalized tonic-clonic and partial seizures. Thus AEPR possesses anticonvulsant property against MES- and PTZ-induced seizures in Wistar rats. However, further research is in progress to isolate the compound responsible for its activity.

Phytoconstituents in the Management of Covid-19: Demystifying the Fact.

The 2019-nCoV (COVID-19; novel coronavirus disease-2019) outbreak is caused by the coronavirus, and its continued spread is responsible for increasing deaths, social and economic burden. COVID-19 created a chaotic situation worldwide and claimed the lives of over 5,027,183 and 248,467,363 confirmed cases have been reported so far as per the data published by WHO (World Health Organization) till 5th November 2021. Scientific communities all over the world are toiling to find a suitable therapeutic drug for this deadly disease. Although till date no promising drug has been discovered for this COVID-19. However, as per the WHO, over 102 COVID-19 vaccines are in clinical development and 185 in pre-clinical development. Naturally occurring phytoconstituents possess considerable chemical richness in the form of anti-viral and anti-parasitic potential and have been extensively exploited for the same globally. Still, phytomedicine-based therapies are considered as the best available treatment option to minimize and treat the symptoms of COVID-19 because of the least possible side effects compared to synthetic drugs recommended by the physicians/clinicians. In this review, the use of plant chemicals as a possible therapeutic agent for severe acute respiratory syndrome coronavirus 2 (SARS CoV2) is highlighted with their proposed mechanism of action, which will prove fruitful and effective in finding a cure for this deadly disease.

Current pharmacological and phytochemical studies of the plant Alpinia galanga.

Traditional medicine systems consist of large numbers of plants with medicinal and pharmacological importance and hence represent an invaluable reservoir of new bioactive molecules. Alpinia galanga (family Zingiberaceae) is commonly known as galangal and has been used for its emmenagogue, aphrodisiac, abortifacient, carminative, antipyretic and anti-inflammatory qualities and used in the treatment of various diseases such as bronchitis, heart diseases, chronic enteritis, renal calculus, diabetes, rheumatism and kidney disorders. It was reported to contain, among other components, essential oils, tannins, phenol, glycosides, monoterpenes and carbohydrates. In the last few years, new compounds such as gallic acid glycoside, galangoisoflavonoid,ß-sitosterol, galangin, alpinin, zerumbone and kampferide have been isolated from various parts of A. galanga. Therefore, the present review is aimed to summarize the information regarding A. galanga concerning the new phytoconstituents and pharmacological uses that have appeared in recent years.

Design, Synthesis and Biological Evaluation of 5-amino-3-aryl-1-(6'-chloropyridazin-3'-yl)pyrazoles and their Derivatives as Analgesic Agents.

An efficient and environmental benign solvent-free synthesis of 5-amino-3-aryl-1-(6'-chloropyridazin-3'-yl)pyrazoles (4A-E): was accomplished by grinding 3-chloro-6-hydrazinopyridazine (2): and ß-ketonitriles (3A-E): in the presence of p-toulenesulfonic acid as a catalyst. Subsequently, 6'-chloro group in 4A-E: was replaced with cyclic 2° amine derivatives viz. pyrrolidine 5A: , piperidine 5B: and morpholine 5C: to obtain 6A-E: , 7A-E: , 8A-E: respectively. The newly synthesized compounds were characterized by using IR, NMR (1H and 13C), mass spectral studies, elemental analyses. All the synthesized compounds were studied for their docking interaction with target protein 6COX and screened for their in vivo analgesic mode of action against swiss albino mice (animal model) using acetic-acid induced writhing test. Consequently, docking simulations data justifies the potential of synthesized series as an analgesic and very well correlated with in vivo study. Preliminary results revealed that most of the synthesized compounds exhibited moderate to good analgesic activity as compared to reference/standard drug (s) sodium diclofenac and candidates 4D: and 7C: protrude out as a promising lead for further investigation.

Synthesis, Computational Studies and Anticonvulsant Activity of Novel Benzothiazole Coupled Sulfonamide Derivatives.

We report herein the synthesis of ¾ substituted benzene sulfonamides linked via phenyl ring to a benzothiazole moiety. The title compounds in the two series namely N-(4-(benzothiazole-2-yl) phenyl) 4- substituted benzene sulfonamides and N-(4-(benzothiazole-2-yl) phenyl) 3- substituted benzene sulfonamides were synthesized by condensing 2-(3/4-aminophenyl) benzothiazole with various substituted sulfonyl chlorides. The synthesized compounds were subjected to neurotoxicity screening, computational studies, and evaluation of their anticonvulsant potential. Amongst all the synthesized compounds, compound 9 emerged as the most potent anticonvulsant agent in maximal electroshock (MES) model (standard: phenytoin) in mice and showed three hydrogen bond interactions with the nicotinic acetylcholine ion gated receptors (PDB ID: 2BG9). Interestingly, compound 13 showed five hydrogen bond interactions with the target protein and thus excellent binding affinity upon computational analysis but was found to be neurotoxic.

Solvent-free synthesis of bacillamide analogues as novel cytotoxic and anti-inflammatory agents.

Synthesis of fourteen analogues of bacillamide, a bioactive tryptamide alkaloid of marine origin, has been accomplished through a highly efficient convergent route. The present solvent-free protocol involves the formation of thiazole ring in the initial step followed by amide coupling between substituted ethyl 2-alkyl/aryl/heteroaryl/amino/aminoarylthiazole-4-carboxylates and tryptamine in presence of 2-hydroxy-4,6-dimethylpyrimidine, a solid phase catalyst to yield N-[2-(1H-indol-3-yl)ethyl]-2-alkyl/aryl/heteroaryl/amino/aminoarylthiazole-4-carboxamides as bacillamide analogues having structural variation at position-2 of thiazole ring. Bacillamide and its analogues were evaluated for their cytotoxic activity against three cancer cell lines (HCT-116, MDA-MD-231 and JURKAT cell lines) using colorimetric cell proliferation assay. Compounds 17a and 17b exhibited potent anti-cell proliferation activity with IC50 values in the range of ∼3.0 µM and ∼0.1-0.6 µM, respectively against these cell lines. Preliminary mechanism of action studies indicates that these compounds initiate caspase dependent apoptosis. Also, compounds 16d, 16f, 17a and 17d exhibited excellent anti-inflammatory activity comparable to well-known NSAID indomethacin and better to bacillamide, when evaluated using carrageenan induced rat hind paw oedema method.

Molecular docking design and one-pot expeditious synthesis of novel 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines as anti-inflammatory agents.

A series of novel 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines were designed as COX-2 inhibitors by molecular docking studies and their synthesis was accomplished via an expeditious one-pot reaction. Structures of the compounds were established by NMR ((1)H-(13)C), IR spectroscopy and high resolution mass spectrometry. All the eleven compounds have been screened for their in vivo anti-inflammatory activity on rats by carrageenan-induced rat paw edema assay. Correlation studies of calculated moldock score and observed percentage inhibition have also been carried out which concluded that the synthesized 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines act as potent anti-inflammatory agents up to the 4th hour of study.

Pharmacophore Modeling and Molecular Docking Studies on Pinus roxburghii as a Target for Diabetes Mellitus.

The present study attempts to establish a relationship between ethnopharmacological claims and bioactive constituents present in Pinus roxburghii against all possible targets for diabetes through molecular docking and to develop a pharmacophore model for the active target. The process of molecular docking involves study of different bonding modes of one ligand with active cavities of target receptors protein tyrosine phosphatase 1-beta (PTP-1ß), dipeptidyl peptidase-IV (DPP-IV), aldose reductase (AR), and insulin receptor (IR) with help of docking software Molegro virtual docker (MVD). From the results of docking score values on different receptors for antidiabetic activity, it is observed that constituents, namely, secoisoresinol, pinoresinol, and cedeodarin, showed the best docking results on almost all the receptors, while the most significant results were observed on AR. Then, LigandScout was applied to develop a pharmacophore model for active target. LigandScout revealed that 2 hydrogen bond donors pointing towards Tyr 48 and His 110 are a major requirement of the pharmacophore generated. In our molecular docking studies, the active constituent, secoisoresinol, has also shown hydrogen bonding with His 110 residue which is a part of the pharmacophore. The docking results have given better insights into the development of better aldose reductase inhibitor so as to treat diabetes related secondary complications.

Ethnobotany and phytopharmacology of Pinus roxburghii Sargent: a plant review.

Traditional medicine is a blend of information gathered over generations from various communities and cultures. Pinus roxburghii Sargent (Pinaceae) commonly known as "chir pine" is widely used in traditional and folkloric systems of medicine. The all parts of the plant are believed to possess medicinal qualities in Ayurvedic and Unani systems of medicine. In these traditional systems of medicine, the plant is used to heal many diseases, including afflictions of the eyes, ears, throat, blood, and skin. The plant parts are rich in various bioactive compounds such as α-pinene, abietic acid, quercetin and xanthone. Resin acids and flavanoid form a major portion of these bioactive compounds. This review presents examples of traditional medicinal uses for P. roxburghii, and subsequently explores the current understanding of the chemical, pharmacological, and biochemical properties of the extracts and the main active constituents found in each tissue of the plant. Clinical trial information is also included where available. Careful evaluation of these data may be helpful for scientists and researchers to discover and evaluate the specific chemical entities responsible for the traditional medicinal uses of P. roxburghii.

Synthesis and pharmacological evaluation of some novel 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles.

A series of novel 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles (6) were synthesized by condensing 3-(2-bromoacetyl)coumarins (4) with various 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides (5), obtained by the reaction of thiosemicarbazide with trifluoromethyl-ß-diketones. All the tested compounds displayed significant to moderate in vivo anti-inflammatory activity when compared to the standard drug indomethacin, and good broad spectrum in vitro antibacterial activity against three Gram-positive and four Gram-negative bacteria when compared with cefixime.

Synthesis, biological evaluation and molecular modeling study of 5-trifluoromethyl-Δ²-pyrazoline and isomeric 5/3-trifluoromethylpyrazole derivatives as anti-inflammatory agents.

Searching for new anti-inflammatory agents, we have prepared a series of potential COX-2 inhibitors, 1-(4,6-dimethylpyrimidin-2-yl)-5-hydroxy-5-trifluoromethyl-Δ(2)-pyrazolines (3) and 1-(4,6-dimethylpyrimidin-2-yl)-3-trifluoromethylpyrazoles (4), by refluxing 2-hydrazino-4,6-dimethylpyrimidine (1) with a number of trifluoromethyl-ß-diketones (2) in ethanol. Further dehydration of compounds (3) to the corresponding 1-(4,6-dimethylpyrimidin-2-yl)-5-trifluoromethylpyrazoles (5) was also achieved. Fifteen of these compounds were screened for their anti-inflammatory activity using the carrageenan-induced rat paw edema assay. While all the compounds exhibited significant anti-inflammatory activity (47-76%) as compared to indomethacin (78%), 3-trifluoromethylpyrazoles (4) were found to be the most effective agents (62-76%). To rationalize this anti-inflammatory activity, docking experiments molecular dynamics simulations were performed to study the ability of these compounds to bind into the active site of the COX-2 enzyme.

Analgesic and Anti-Inflammatory Activity of Pinus roxburghii Sarg.

The Chir Pine, Pinus roxburghii, named after William Roxburgh, is a pine native to the Himalaya. Pinus roxburghii Sarg. (Pinaceae) is traditionally used for several medicinal purposes in India. As the oil of the plant is extensively used in number of herbal preparation for curing inflammatory disorders, the present study was undertaken to assess analgesic and anti-inflammatory activities of its bark extract. Dried and crushed leaves of Pinus roxburghii Sarg. were defatted with petroleum ether and then extracted with alcohol. The alcoholic extract at the doses of 100 mg/kg, 300 mg/kg, and 500 mg/kg body weight was subjected to evaluation of analgesic and anti-inflammatory activities in experimental animal models. Analgesic activity was evaluated by acetic acid-induced writhing and tail immersion tests in Swiss albino mice; acute and chronic anti-inflammatory activity was evaluated by carrageenan-induced paw oedema and cotton pellet granuloma in Wistar albino rats. Diclofenac sodium and indomethacin were employed as reference drugs for analgesic and anti-inflammatory studies, respectively. In the present study, the alcoholic bark extract of Pinus roxburghii Sarg. demonstrated significant analgesic and anti-inflammatory activities in the tested models.

Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents.

A new series of pyrazolylpyrazolines (5a-k) was synthesized by the reaction of appropriate chalcones (3a-k) with 4-hydrazinobenzenesulfonamide hydrochloride (4) in ethanol. All the newly synthesized target compounds (5a-k) were screened for their anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compounds 5g and 5j showed pronounced anti-inflammatory activity comparable to the reference standard nimesulide, whereas, compounds 5b, 5d and 5h displayed good anti-inflammatory activity. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity against two Gram-positive bacteria and two Gram-negative bacteria. Four compounds 5c, 5h-5j showed good broad spectrum activity against all the tested Gram-positive and Gram-negative bacterial strains. Compound 5j could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory and antibacterial profile.

Ethnobotany and phytopharmacology of Pinus roxburghii Sargent: a plant review / 中西医结合学报

Traditional medicine is a blend of information gathered over generations from various communities and cultures. Pinus roxburghii Sargent (Pinaceae) commonly known as "chir pine" is widely used in traditional and folkloric systems of medicine. The all parts of the plant are believed to possess medicinal qualities in Ayurvedic and Unani systems of medicine. In these traditional systems of medicine, the plant is used to heal many diseases, including afflictions of the eyes, ears, throat, blood, and skin. The plant parts are rich in various bioactive compounds such as α-pinene, abietic acid, quercetin and xanthone. Resin acids and flavanoid form a major portion of these bioactive compounds. This review presents examples of traditional medicinal uses for P. roxburghii, and subsequently explores the current understanding of the chemical, pharmacological, and biochemical properties of the extracts and the main active constituents found in each tissue of the plant. Clinical trial information is also included where available. Careful evaluation of these data may be helpful for scientists and researchers to discover and evaluate the specific chemical entities responsible for the traditional medicinal uses of P. roxburghii.