Exploring the influence of steric, electronic and lipophilic descriptors of 1,3-diarly propenones on their anti-inflammatory activity

BACKGROUND AND THE PURPOSE OF THE STUDY: Various compounds from natural and synthetic origins containing the 1,3-diarylpropenone structure have been reported to produce a variety of biological activities like anti-microbial, anti-inflammatory, vascular muscle relaxant, etc. A systematic analysis of the structural features responsible for anti-inflammatory activity and a possible mode of their actions were proposed to be evaluated by synthesizing a set of compounds, screening them for anti-inflammatory activity and developing a QSAR model. METHODS: Two types of 1,3-diarylpropenone derivatives were synthesized employing the Claisen-Schmidt condensation. These compounds were then screened for their in vivo anti- inflammatory activity by the carrageenin induced rat paw edema method and also for in vitro cyclooxygenase-2 (COX-2) inhibition activity using a colorimetric kit for COX (ovine) inhibitor screening assay. These derivatives and their anti-inflammatory activity data were employed for QSAR analysis on Vlife MDS 3.5 software. The molecules were divided into training and test sets based on observed activity and QSAR models were generated for the training set and validated. The activity of the molecules of the test set was predicted according to the QSAR equation fit. Possible correlation between observed anti-inflammatory activity and in vitro cyclooxygenase-2 inhibition was also studied. RESULTS AND CONCLUSION: Insignificant difference between the observed and predicted biological activity revealed that the selected electronic, steric and lipophilic parameters have a significant correlation (r(2)=0.85) with anti-inflammatory activity of the selected class of compounds. On the basis of results it may be suggested that the 1,3-diaryl-2-propen-1-ones framework is an attractive template for structural optimization to achieve better potency of anti-inflammatory activity. Similarly, the relatively low correlation between anti-inflammatory activity and cyclooxygenase-2 inhibition indicates that other modes of actions may also be responsible for the anti-inflammatory activity of the tested compounds.     

New thiazolidinyl analogs containing pyridine ring: synthesis, biological evaluation and QSAR studies

A series of pyridine derivatives of thiazolidin-4-ones (4a–4o) has been synthesized. Structures of these compounds were established on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectral data. All the synthesized compounds have been evaluated for their anti-inflammatory and analgesic effects. The results showed that compound 2-[4-methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-1,3-thiazolidin-4-one (4d), 2-(2,4-dinitro-phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4h), and 2-[3-nitro-phenylimino]-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4j) exhibited good anti-inflammatory and analgesic activity. Compound 4h was found to be the most active compound of the series with an interesting dual anti-inflammatory and analgesic activity. Docking simulation was performed to position synthesized compounds into the active site of COX-2. The relationships of energy-based docking score with analgesic and anti-inflammatory activities were also investigated by linear regression method. The QSAR models with R ² of 0.621 and 0.740 were developed for analgesic and anti-inflammatory activities, respectively.     

Synthesis of (Z)-1,3-diaryl-2-(4-aryl-1H-1,2,3-triazol-1-yl)prop-2-en-1-ones and their antibacterial studies

The cyclization of 1,3-diaryl-2-azido-2-propen-1-ones with various alkynes in the presence of a catalytic amount of copper sulfate–sodium ascorbate in DMSO–water mixture under microwave irradiation led to the formation of (Z)-1,3-diaryl-2-(4-substituted-1H-1,2,3-triazol-1-yl)prop-2-en-1-ones. The structure and stereochemistry of the products have been elucidated by spectroscopic and single crystal X-ray analyses. All the newly synthesized compounds have been tested for their antibacterial activity against four strains of bacteria and found to have moderate to good inhibition.     

Synthesis,analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles

Background

Long-term clinical employment of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant side effects including gastrointestinal (GI) lesions and kidney toxicity. In this paper we designed and synthesized new imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles by molecular hybridization of previously described anti-inflammatory compounds in the hope of obtaining new safer analgesic and anti-inflammatory agents.

Methods

The target structures were synthesized by preparation of 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 5. The reaction of hydrazine hydrate with this ester afforded the 5-methyl-1H-imidazole-4-carboxylic acid hydrazide 6 which was converted to target compounds 7-15 according to the known procedures. In silico toxicity risk assessment and drug likeness predictions were done, in order to consider the privileges of the synthesized structures as drug candidates.

Results and discussion

The analgesic and anti-inflammatory profile of the synthesized compounds were evaluated by writhing and carrageenan induced rat paw edema tests respectively. Compounds 8, 9 and 11-13 and 15 were active analgesic agents and compounds 8, 9 and 11-13 showed significant anti-inflammatory response in comparison with control. Compounds 11 and 13 were screened for their ulcerogenic activities and none of them showed significant ulcerogenic activity. The active Compounds 11 and 12 showed the highest drug likeness and drug score.

Conclusions

The analgesic and anti-inflammatory activities of title compounds were comparable to that of standard drug indomethacin with a safer profile of activity. The results revealed that both of oxadiazole and triazole scaffolds can be determined as pharmacophores. The in silico predictions and pharmacological evaluations showed that compounds 11 and 12 can be chosen as lead for further investigations.     

Synthesis and anti-inflammatory activity of 3,3a-dihydro-2H,9H-isoxazolo [3,2-b] [1,3]benzoxazin-9-ones and related compounds.

A series of 3,3a-dihydro-2H,9H-isoxazolo[3,2-b]-[1,3]benzoxazin-9-ones was synthesized and evaluated for anti-inflammatory, antipyretic and analgesic activity. Since many of these compounds exhibited promising activity, particularly in the anti-inflammatory tests, a number of homologous 2,3,4,4a-tetrahydro-10H-1,2-oxazino[3,2-b]-[1,3]benzoxazin-10-ones and one 3,4,5,5a-tetrahydro-2H, 11H,-1,2-oxazepino [3,2-b][1,3]benzoxazin-11-one, the 9-chloro analog, were also prepared and evaluated. The expanded ring members were generally less active than the tricyclic compounds containing the isoxazolidine ring.     

Synthesis of new thiazolo[3,2-b][1,2,4]triazole-6(5H)-one derivatives as potent analgesic and anti-inflammatory agents

A series of thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones were synthesized and evaluated for their analgesic and anti-inflammatory activities. The structures of these compounds were supported by FT-IR, ¹HNMR, and Mass spectra. All of the final compounds showed potent analgesic activity and the best compound 9d was 2.4 times more potent than mefenamic acid as the reference drug. In addition, most of them showed comparable or better anti-inflammatory activity in comparison with mefenamic acid and indomethacin. Moreover, compounds 9d, 9e, 9g, 9h, 9i, 9k, 9n, and 9o did not exhibit any significant ulcerogenic activity.     

Design, synthesis, anti-inflammatory, analgesic screening, and molecular docking of some novel 2-pyridyl (3H)-quinazolin-4-one derivatives

A novel series of 6-bromo-2-(4-pyridyl)-quinazolin-4(3H)-ones were synthesized by reacting 5-bromo anthranilic acid with isonictinoly chloride in the presence of acetic anhydride, which were further reacted with p-amino acetophenone to obtain 3-(4-acetylphenyl)-6-bromo-2-(pyridin-4-yl)quinazolin-4(3H)-one (3). Compound 3 underwent further reactions with different aldehydes to afford chalcone derivatives 4–10, which in turn underwent various cyclization reactions to afford cyclized products 15–18. 2-aminothiazole derivatives 12 obtained by reaction of 3 with bromine then with thiourea. Compound 14 obtained by treatment of 11 with KSCN followed by cyclization. Some of the synthesized compounds 4, 5, 12, 14, 15 and 18 were screened for both analgesic and anti-inflammatory activities. All tested compounds showed good analgesic and anti-inflammatory activity in comparison to the reference standard indomethacin. Compounds 4 and 5 showed the highest anti-inflammatory activity, while compounds 14 and 15 showed the highest analgesic activity among all the tested compounds.     

Sydnone derivatives. Part VII: Synthesis of some novel thiazoles and their pharmacological properties.

The synthesis of some 4-(arylsydnonyl)-2-(4-arylhydrazono-3-methyl-5-oxo-2-pyrazolin-1-yl)- thiazoles by reacting 1-thiocarboxamido-3-methyl-4-(aryihydrazono)-2-pyrazolin-5-ones with different 4-bromoacetyl-3-arylsydnones is described. A few compounds from this series were screened for their anti-inflammatory, analgesic, and CNS depressant activities. Among the tested compounds 6s, 6d, 6n, and 6u showed significant anti-inflammatory activity comparable with that of standard drug Ibuprofen. Compounds containing chlorine and carboxylic substituents are more active. 6f, 6r, and 6u showed marked analgesic activity and most of the compounds tested showed promising CNS depressant activity comparable with that of standard drug pentobarbitone.     

Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.     

PEG Mediated Synthesis and Biological Evaluation of Asymmetrical Pyrazole Curcumin Analogues as Potential Analgesic,Anti-Inflammatory and Antioxidant Agents

The new series of asymmetrical pyrazole curcumin analogues 4a – g were synthesized by using polyethylene glycol (PEG-400) as a green reaction medium and evaluated for their in vivo analgesic and in vitro antioxidant (H₂O₂, DPPH, Ferrous reducing power and Nitric oxide scavenging activity) and anti-inflammatory activities. All the compounds synthesized 4a – g showed the potential to demonstrate analgesic activity as compared to the standard ibuprofen. Among the tested series, compounds 4e and 4b exhibited good hydrogen peroxide scavenging activity as compared to the standard butylated hydroxy toluene (BHT). Compounds 4b , 4d , 4f , and 4g showed good DPPH free radical scavenging activity. Compounds 4b , 4c , 4d , 4e and 4g showed excellent ferrous-reducing power activity, whereas all the compounds showed better nitric oxide scavenging activity than standard ascorbic acid. Additionally, all the synthesized compounds were also screened for their in vitro anti-inflammatory activity. Compounds 4b , 4d , 4f and 4g showed good anti-inflammatory activity as compared to standard diclofenac sodium.     

A study of anti-inflammatory activity of some novel alpha-amino naphthalene and beta-amino naphthalene derivatives

In the present study, some naphthalene derivatives have been synthesized by incorporating azetidinyl and thiazolidinyl moieties at its alpha- or beta-positions such as alpha-(3-chloro-2-oxo-4-substituted)aryl-1-azetidinyl)naphthalenes 6-10, alpha-((substituted)aryl-4-oxo-1,3-thiazolidin-3-yl)naphthalenes 11-15, beta-(3-chloro-2-oxo-4-substituted aryl-1-azetidinyl)naphthalenes 21-25, and beta-(substituted aryl-4-oxo-1,3-thiazolidin-3-yl)naphthalenes 26-30. These compounds have also been screened for acute toxicity and anti-inflammatory and analgesic activities. Compounds which showed better anti-inflammatory and analgesic activities were also examined for their ulcerogenic liability and underwent a cyclooxygenase assay. Two compounds, 12 and 28, were found to exhibit potent anti-inflammatory activity as compared to the standard drugs phenylbutazone and naproxen.     

Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-butyl-3-substituted quinazolin-4-(3H)-ones

A variety of novel 2-butyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by reacting (2-butyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with a variety of amines; the starting material dithiocarbamate was synthesized from anthranilic acid. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. While the test compounds exhibited significant activity, compounds A1, A2, A3 and A4 showed more potent analgesic activity and compound A4 showed more potent anti-inflammatory activity than the reference diclofenac sodium.     

Lonazolac analogues: molecular modeling, synthesis, and in vivo anti-inflammatory activity

A novel series of 1,3-diarylpyrazole derivatives (4–8), analogues to lonazolac, were designed, synthesized, and evaluated for their anti-inflammatory as well as analgesic activities. To target preferential cyclooxygenase-2 (COX-2) inhibitors, the design of these compounds was based upon two different molecular modeling studies. The first study included fit-comparison study of conformational models of compounds 4–8 with a novel validated COX-2 inhibitors hypothesis generated from the corresponding leads I–V using Hip-Hop CATALYST software. The second study included docking study of the designed compounds 4–8 with binding site of COX-1 and COX-2 enzymes using internal coordinate mechanics (ICM)-Pro software. The reported Akaho method was then used to predict the COX-2 preferentiality of the designed compounds. The designed molecules were synthesized and screened for in vivo anti-inflammatory and analgesic activity. Compounds 4a, 6a, and 8b showed high activity in comparison with indomethacin, consistent with virtual molecular modeling studies.     

Synthesis, characterization, and biological evaluation of certain 1,3-thiazolone derivatives bearing pyrazoline moiety as potential anti-breast cancer agents

A series of 5-arylidene-2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-1,3-thiazol-4(5H)-ones were synthesized and screened for their in vitro antitumor activity against human breast adenocarcinoma cell line (MCF-7). Five of the test compounds exhibited good antitumor activity superior to the reference drug, doxorubicin, with IC₅₀ range 1.4–2.3 μM. Among the test compounds, 2-[3,5-bis(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-5-(2-methoxybenzylidene)-1,3-thiazol-4(5H)-one (3i) was found to show the most potent anticancer activity.     

Synthesis and pharmacological evaluation of some 3-(4-methylphenyl)-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents

A variety of 3-(4-methyl phenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-methyl phenyl)-3H-quinazolin-4-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(4-methyl phenyl)-3H-quinazolin-4-one was synthesized from 4-methyl aniline. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic index activities. While the test compounds exhibited significant activity, compounds Al, A2, and A3 showed more potent analgesic activity and the compound A3 showed more potent anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

Synthesis of novel 1-pyrazolylpyridin-2-ones as potential anti-inflammatory and analgesic agents

A new series of 4-alkyl/aryl-2-oxo-1-pyrazolyl-1,2-dihydropyridine-3-carbonitriles, pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their anti-inflammatory and analgesic activities. Among the tested compounds, 3e and 8b exhibited comparable anti-inflammatory activity to the standard (indomethacin). Compounds 5, 7a, and 8b displayed potent analgesic activity. Detailed syntheses, spectroscopic and biological data are reported.     

Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives

In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new compounds with potential analgesic and anti-inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12-14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose-dependent anti-inflammatory activity. The best dual analgesic / anti-inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.     

Antiinflammatory, Analgesic and Antipyretic Activity of Certain Thiazolidinones

The thiazolidin-4-one derivatives and the corresponding spiro compounds were synthesized from sulphanilamide and were evaluated for anti-inflammatory and analgesic activity in acute and sub acute models. Compounds were also evaluated for antipyretic and cyclooxygenase enzyme inhibitory activity. All the compounds showed significant antiinflammatory, analgesic and antipyretic activity at 100 mg/kg in all the models. The compounds B1, B2, B5, B6, and B8 showed maximum inhibition of COX-2 activity without inhibiting the COX-1 activity. The nimesulide was used as standard drug for comparison. The substitution at R, R₁ and R₂ with the functional groups Cl, OCH₃, NO₂ and OH in the aromatic ring resulted in increased activity as compared to unsubstituted thiazolidin-4-ones. However the substitution at R₃ with spiro group did not improve the activity. The study suggests that COX-2 binding site may not be a rigid structure but might adopt to various related molecules.     

Synthesis,analgesic, anti-inflammatory and antibacterial activities of some novel 2-phenyl-3-substituted quinazolin-4(3H) ones

A series of novel 2-phenyl-3-substituted quinazolin-4(3H)-ones have been synthesized by treating methyl-N-(2-phenyl quinazolin-3-yl-4(3H)-one) dithiocarbamate with different amines, the starting material dithiocarbamate was synthesized from anthranilic acid. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. All the test compounds exhibited significant activity, the compounds A1, A2 and A3 shown more potent analgesic activity, and the compound A3 shown more potent anti-inflammatory activity than the reference standard diclofenac sodium.     

Design, synthesis, antimicrobial, anticancer evaluation, and QSAR studies of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones

A series of 4-(substituted benzylidene-amino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-ones (1–17) was synthesized and tested in vitro for its antimicrobial and anticancer potentials. The biological screening results indicated that compounds having m-chloro substituent on benzaldehyde portion showed antimicrobial potential, whereas compounds having chloro, methoxy, and hydroxyl groups showed anticancer potential. The quantitative structure activity relationship (QSAR) studies indicated the importance of topological parameter, valence first order molecular connectivity index in describing antifungal activity. The developed QSAR models, however, were statistically insignificant with reference to anticancer activity of the synthesized compounds.