Hybrid Compounds Strategy in the Synthesis of Oleanolic Acid Skeleton-NSAID Derivatives

Pawełczyk, Anna; Olender, Dorota; Sowa-Kasprzak, Katarzyna; Zaprutko, Lucjusz

doi:10.3390/molecules21040420

Cited by 21 publications

(18 citation statements)

References 17 publications

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“…For the commercial NSAIDs, no significant difference was observed (p < 0.05). Regarding the oleanolic acid derivatives (12)(13)(14)(15), oleanoyl ibuprofenate (12) showed the highest inhibitory effect of the series, showing better activity than the parent compound oleanolic acid (3). In the imbricatol derivatives (8)(9)(10)(11), the compound imbricatol-15-yl naproxenate (10) showed an increase in the COX-2 inhibitory activity compared to the parent compound naproxen (5) (p < 0.05).…”

Section: Enzyme Inhibition Activitymentioning

confidence: 98%

“…In the imbricatol derivatives (8)(9)(10)(11), the compound imbricatol-15-yl naproxenate (10) showed an increase in the COX-2 inhibitory activity compared to the parent compound naproxen (5) (p < 0.05). Regarding the oleanolic acid derivatives (12)(13)(14)(15), oleanoyl ibuprofenate (12) showed the highest inhibitory effect of the series, showing better activity than the parent compound oleanolic acid (3). In the ibuprofen derivatives, the activity was lower than that of the synthetic anti-inflammatory drug alone (57.3%).…”

Section: Enzyme Inhibition Activitymentioning

confidence: 99%

“…The design of hybrid compounds including synthetic moieties and NSAIDs has been explored, including the hybrids of Aspirin ® , [11] and new compounds including terpene moieties. [12] We have previously reported the in vivo antiinflammatory effect of hybrid molecules of terpenes and two synthetic anti-inflammatory agents in the ear edema model in mice. [13] However, the activity of these synthetic derivatives on key enzymes associated with the inflammatory response is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies

et al. 2018

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The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The antiinflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX-2, and in silico docking studies in 15-LOX and COX-2. The synthesized hybrids showed an inhibition of COX-2 and LOX between 9.8%-57.4% and 0.0%-97.7%, respectively. None of the hybrids showed an improvement in the inhibitory effect toward these pro-inflammatory enzymes, compared to the parent terpenes and non-steroidal anti-inflammatory drugs. The docking studies allowed us to predict the potential binding modes of hybrids 6-15 within COX-2 and 15-LOX active sites.The relative affinity of the compounds inside the binding sites could be explained by forming non-covalent interactions with most important and known amino acids reported for those enzymes. A good correlation (r 2 = 0.745) between docking energies and inhibition percentages against COX-2 was found. The high inhibition obtained for compound 10 against COX-2 was explained by hydrogen bond interactions at the enzyme binding site. New synthetic possibilities could be obtained from our in silico models, improving the potency of these hybrid compounds. K E Y W O R D Santi-inflammatory activity, computational analysis, COX-2 and 15-LOX inhibition, ibuprofen and naproxen terpenyl hybrids, in silico studies

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Section: Enzyme Inhibition Activitymentioning

confidence: 98%

Section: Enzyme Inhibition Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies

et al. 2018

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“…Terpene hybrids reported in bibliography include hybrids between terpene-benzoylphenyl urea (BPU) [ 27 ], hybrid terpene-amino acid [ 28 , 29 ], hybrid terpene-quinone [ 17 , 30 ], hybrid terpene-anti-inflammatory agents [ 31 ], hybrid terpene-NSAID [ 32 ], among others. However, to date there is little information on the possible biological effect that hybrid molecules formed by the fusion of two different terpenes may have.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antiviral and Cytotoxic Activity of Novel Terpenyl Hybrid Molecules Prepared by Click Chemistry

et al. 2018

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Naturally occurring terpenes were combined by click reactions to generate sixteen hybrid molecules. The diterpene imbricatolic acid (IA) containing an azide group was used as starting compound for the synthesis of all the derivatives. The alkyne group in the terpenes cyperenoic acid, dehydroabietinol, carnosic acid γ-lactone, ferruginol, oleanolic acid and aleuritolic acid was obtained by esterification using appropriate alcohols or acids. The hybrid compounds were prepared by combining the IA azide function with the different terpene-alkynes under click chemistry conditions. The cytotoxic activity of the terpene hybrids 1–16 was assessed against Vero cells and tumour cell lines (HEP-2, C6 and Raw 264.7). Compounds 1, 2, 3 and 7 showed cytotoxic activity against the tested cell lines. The antiviral activity of the compounds was evaluated against HSV-1 KOS, Field and B2006 strain. For the pairs of hybrid compounds formed between IA-diterpene (compounds 3–8, except for compound 7), a moderate activity was observed against the three HSV-1 strains with an interesting selectivity index (SI ≥10, SI = CC50/CE50) for some compounds.

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“…15 In molecular hybridization constituents are linked directly, with the help of some linker, or the active structural parts are merged into a single molecule. 16 In our work, we studied the hybrid molecules prepared by a combination of NSAIDs with other synthetic and natural molecules. Moreover, the combination of different pharmacophores other than NSAIDs having analgesic and antiinflammatory activities is also discussed.…”

Section: Introductionmentioning

confidence: 99%

Hybrid organic molecules as antiinflammatory agents; a review of structural features and biological activity

Mohsin¹,

Ahmad²

2018

Turk J Chem

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Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation.Some undesirable effects are linked with NSAIDs such as the gastrointestinal tract (GIT) toxicity and cardiovascular disturbances. At present the preparation of a hybrid molecular technique is being used to produce new analgesic and antiinflammatory molecules. Attachment of NSAIDs with nitric oxide and hydrogen sulfide releasing molecules produced some gastroprotective agents with improved analgesic and antiinflammatory activities. Combination of NSAIDs with different biologically active 5-membered, 6-membered, and condensed heterocyclic rings has also led to the formation of some potent molecules. Some of these hybrid molecules, e.g., ibuprofen-thiazole, exhibited less GIT toxicity, while others showed selectivity for COX-2 enzyme, e.g., quinazolinone-pyrimidine and benzothiophene-rhodanine hybrids. COX-2 selectivity was also exhibited by hybrids of NSAIDs with natural molecules such as salicylates-resveratrol, chromoneoxindole, and chrysin-indole-pyrazole. The preparation of new hybrid molecules is significant because they can serve as a lead compound for the discovery and development of safer analgesic and antiinflammatory agents.

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Hybrid Compounds Strategy in the Synthesis of Oleanolic Acid Skeleton-NSAID Derivatives

Cited by 21 publications

References 17 publications

Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies

Inhibition of key enzymes in the inflammatory pathway by hybrid molecules of terpenes and synthetic drugs: In vitro and in silico studies

Synthesis, Antiviral and Cytotoxic Activity of Novel Terpenyl Hybrid Molecules Prepared by Click Chemistry

Hybrid organic molecules as antiinflammatory agents; a review of structural features and biological activity

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