Valentina Onnis | Università degli Studi di Cagliari (original) (raw)
Papers by Valentina Onnis
![Research paper thumbnail of Products derived from the reaction of [M(CN)4O(H2O)]2− with pentane-2,4-dione. X-ray crystal structure of (Ph4P)2[M(CN)3O(acac)], M = Mo or W](https://attachments.academia-assets.com/103743644/thumbnails/1.jpg)
](Transition Metal Chemistry, 2001
The reaction of pentane-2,4-dione (Hacac) with [M(CN)4O(H2O)]2- ion (M = Mo, W) gave complexes wh... more The reaction of pentane-2,4-dione (Hacac) with [M(CN)4O(H2O)]2- ion (M = Mo, W) gave complexes which were isolated as their tetraphenylphosphonium salts (Ph4P)2[M(CN)3O(acac)], and were characterised by X-ray crystal structure determination, by u.v.–vis. and 1H-n.m.r. spectroscopy, cyclic voltammetry, and thermogravimetric and differential thermal analysis. The structure determination showed the complexes to have an approximately octahedral geometry, with the three cyanides in
Bioorganic Chemistry
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Bioorganic & medicinal chemistry, 2013
We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxyb... more We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI50 values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.
PLOS ONE, 2016
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is a... more Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro-and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.
PloS one, 2015
Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate se... more Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl)-N-(3-methylpyridin-2-yl)propanamide (Flu-AM1). These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known. COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG) as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA) as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon γ- stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manne...
Pest Management Science, 2015
BACKGROUND: With the ultimate goal of identifying new compounds active against rootknot nematodes... more BACKGROUND: With the ultimate goal of identifying new compounds active against rootknot nematodes, a set of 14 substituted chalcones were synthesised starting from acetophenones. These chalcones and various acetophenones were tested in vitro against Meloidogyne incognita. RESULTS: The most potent acetophenones were 4-nitroacetophenone and 4iodoacetophenone with EC 50/24h values of 12 ± 5 and 15 ± 4 mg/L, respectively, somewhat weaker than that of the chemical control fosthiazate in our previous experiments (EC 50/24h 0.4 ± 0.3 mg/L). When we converted the acetophenones to chalcones, the nematicidal activity differed based on their substitution pattern. The condensation of 4-nitroacetophenone with 2,4,6-trihydroxybenzaldehyde to give the corresponding chalcone (E)-1-(4-nitrophenyl)-3-(2,4,6-trihydroxyphenyl)prop-2-en-1-one (11) led to a slight reduction in activity (EC 50/24h value 25 ±17 mg/L). Moreover, (E)-3-(2-hydroxy-5-iodophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (26) showed better activity (EC 50/24h value 26 ± 15 mg/L) when compared to 4methoxyacetophenone (EC 50/24h value 43 ± 10 mg/L). CONCLUSIONS: Acetophenones and chalcones may represent good leads in the discovery of new nematicidal compounds and may have potential use in crop management as active ingredients.
Journal of Heterocyclic Chemistry, 1995
Journal of Heterocyclic Chemistry, 2000
2,4-Diamino-6-methylthiopyrimidines 1 reacted with sodium methoxyde and benzylamine to give the c... more 2,4-Diamino-6-methylthiopyrimidines 1 reacted with sodium methoxyde and benzylamine to give the corresponding 6-methoxypyrimidine and 6-benzylaminopyrimidine derivatives 2 and 4 respectively. The reaction of 1 with hydrazine hydrate, in ethanol, gave 6-hydrazino derivatives 6. However, by treating pyrimidines 1 in boiling hydrazine hydrate 3,6-diamino-4-hydrazino-1H-pyrazolo[3,4-d]pyrimidine 5 was obtained. The 6-hydrazinopyrimidines 6 could be converted into the pyrazolo[3,4-d], triazolo[4,3-c] and tetrazolo-[1,5-c]pyrimidines 7, 8 and 9 by the action of heating, trimethyl orthoformate and nitrous acid, respectively.
Pharmaceuticals, 2022
The Enterovirus genus includes many viruses that are pathogenic in humans, including Coxsackie vi... more The Enterovirus genus includes many viruses that are pathogenic in humans, including Coxsackie viruses and rhinoviruses, as well as the emerging enteroviruses D68 and A71. Currently, effective antiviral agents are not available for the treatment or prevention of enterovirus infections, which remain an important threat to public health. We recently identified a series of quinoxaline derivatives that were provento be potent inhibitors of coxsackievirus B5, the most common and a very important human pathogen belonging to the enterovirus genus. We have shown how most active derivatives interfere with the earliest stages of viral replication, blocking infection. Considering the broad antiviral spectrum, a very attractive property for an antiviral drug, we aimed to investigate the antiviral activity of the most promising compounds against other Enterovirus species. Here, we investigated the susceptibility of a panel of representatives of Enterovirus genus (enterovirus A71, belonging to A ...
European Journal of Medicinal Chemistry, 2018
Journal of Enzyme Inhibition and Medicinal Chemistry
Supporting Informations Figure S1. Superposition between: (A) The crystallographic pose of QK5 (c... more Supporting Informations Figure S1. Superposition between: (A) The crystallographic pose of QK5 (cyan sticks) and the lowest IFDScore binding prediction (pink sticks) (RMSD: 0.58). (B) The binding mode of Ibu-AM5 found after MDs [1] (violet sticks) and the best IFDScore solution found by the IFD protocol (green sticks) (RMSD: 1.34).
Metabolites
The tumor microenvironment is crucial for the growth of cancer cells, triggering particular bioch... more The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identifica...
Molecules
The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant... more The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by ...
Journal of Enzyme Inhibition and Medicinal Chemistry
Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by n... more Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by nonsteroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)À2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [ 3 H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a K i value of 0.26 mM and an a value of 4.9. At a concentration of 10 mM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
Proceedings of 4th International Electronic Conference on Medicinal Chemistry
Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysi... more Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysis of the fatty acid ethanolamide family of signaling lipids, which includes anandamide (AEA), an endogenous ligand for cannabinoid receptors. Endogenous FAAH substrates such as AEA serve key regulatory functions in the body and have been implicated in a variety of pathological conditions including pain, inflammation, sleep disorders, anxiety, depression, and vascular hypertension, and there has been an increasing interest in the development of inhibitors of this enzyme. Different structural classes of FAAH inhibitors have been reported including aketoheterocycles, (thio)hydantoins, piperidine/piperazine ureas, and carbamate derivatives. When tested, these compounds have been shown to be efficacious in models of inflammatory, visceral, and in some cases neuropathic pain without producing the central effects seen with directly acting cannabinoid receptor agonists. An intriguing aspect of FAAH inhibition is that some currently marketed nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to be weak inhibitors of FAAH, but can be used as a template for the design of more potent compounds. However, structure-activity relationships of analogues of clinically used NSAIDs with respect to FAAH inhibition have been examined scarcely in the literature. These findings led us to design and synthesis of new series of FAAH inhibitors derivable from conjugation of heterocyclic structures with NSAIDs as profens, fenamates, and new their correlate molecules. In this keynote we report on the synthetic pathways to transform old analgesic drugs into FAAH inhibitors and SAR studies on the new inhibitor series.
ChemInform
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Pathogens and Disease
Pyrrolyl heteroarylcarbothioamide derivatives are new dual inhibitors of both ribonuclease H and ... more Pyrrolyl heteroarylcarbothioamide derivatives are new dual inhibitors of both ribonuclease H and polymerase HIV-1 RT-associated functions, a new promising resource against drug resistance.
Transition Metal Chemistry, 2001
The reaction of pentane-2,4-dione (Hacac) with [M(CN)4O(H2O)]2- ion (M = Mo, W) gave complexes wh... more The reaction of pentane-2,4-dione (Hacac) with [M(CN)4O(H2O)]2- ion (M = Mo, W) gave complexes which were isolated as their tetraphenylphosphonium salts (Ph4P)2[M(CN)3O(acac)], and were characterised by X-ray crystal structure determination, by u.v.–vis. and 1H-n.m.r. spectroscopy, cyclic voltammetry, and thermogravimetric and differential thermal analysis. The structure determination showed the complexes to have an approximately octahedral geometry, with the three cyanides in
Bioorganic Chemistry
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Bioorganic & medicinal chemistry, 2013
We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxyb... more We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI50 values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.
PLOS ONE, 2016
Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is a... more Neuropathic pain is a severe diabetes complication and its treatment is not satisfactory. It is associated with neuroinflammation-related events that participate in pain generation and chronicization. Prokineticins are a new family of chemokines that has emerged as critical players in immune system, inflammation and pain. We investigated the role of prokineticins and their receptors as modulators of neuropathic pain and inflammatory responses in experimental diabetes. In streptozotocin-induced-diabetes in mice, the time course expression of prokineticin and its receptors was evaluated in spinal cord and sciatic nerves, and correlated with mechanical allodynia. Spinal cord and sciatic nerve pro-and anti-inflammatory cytokines were measured as protein and mRNA, and spinal cord GluR subunits expression studied. The effect of preventive and therapeutic treatment with the prokineticin receptor antagonist PC1 on behavioural and biochemical parameters was evaluated. Peripheral immune activation was assessed measuring macrophage and T-helper cytokine production. An up-regulation of the Prokineticin system was present in spinal cord and nerves of diabetic mice, and correlated with allodynia. Therapeutic PC1 reversed allodynia while preventive treatment blocked its development. PC1 normalized prokineticin levels and prevented the up-regulation of GluN2B subunits in the spinal cord. The antagonist restored the pro-/anti-inflammatory cytokine balance altered in spinal cord and nerves and also reduced peripheral immune system activation in diabetic mice, decreasing macrophage proinflammatory cytokines and the T-helper 1 phenotype. The prokineticin system contributes to altered sensitivity in diabetic neuropathy and its inhibition blocked both allodynia and inflammatory events underlying disease.
PloS one, 2015
Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate se... more Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl)-N-(3-methylpyridin-2-yl)propanamide (Flu-AM1). These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known. COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG) as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA) as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon γ- stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manne...
Pest Management Science, 2015
BACKGROUND: With the ultimate goal of identifying new compounds active against rootknot nematodes... more BACKGROUND: With the ultimate goal of identifying new compounds active against rootknot nematodes, a set of 14 substituted chalcones were synthesised starting from acetophenones. These chalcones and various acetophenones were tested in vitro against Meloidogyne incognita. RESULTS: The most potent acetophenones were 4-nitroacetophenone and 4iodoacetophenone with EC 50/24h values of 12 ± 5 and 15 ± 4 mg/L, respectively, somewhat weaker than that of the chemical control fosthiazate in our previous experiments (EC 50/24h 0.4 ± 0.3 mg/L). When we converted the acetophenones to chalcones, the nematicidal activity differed based on their substitution pattern. The condensation of 4-nitroacetophenone with 2,4,6-trihydroxybenzaldehyde to give the corresponding chalcone (E)-1-(4-nitrophenyl)-3-(2,4,6-trihydroxyphenyl)prop-2-en-1-one (11) led to a slight reduction in activity (EC 50/24h value 25 ±17 mg/L). Moreover, (E)-3-(2-hydroxy-5-iodophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (26) showed better activity (EC 50/24h value 26 ± 15 mg/L) when compared to 4methoxyacetophenone (EC 50/24h value 43 ± 10 mg/L). CONCLUSIONS: Acetophenones and chalcones may represent good leads in the discovery of new nematicidal compounds and may have potential use in crop management as active ingredients.
Journal of Heterocyclic Chemistry, 1995
Journal of Heterocyclic Chemistry, 2000
2,4-Diamino-6-methylthiopyrimidines 1 reacted with sodium methoxyde and benzylamine to give the c... more 2,4-Diamino-6-methylthiopyrimidines 1 reacted with sodium methoxyde and benzylamine to give the corresponding 6-methoxypyrimidine and 6-benzylaminopyrimidine derivatives 2 and 4 respectively. The reaction of 1 with hydrazine hydrate, in ethanol, gave 6-hydrazino derivatives 6. However, by treating pyrimidines 1 in boiling hydrazine hydrate 3,6-diamino-4-hydrazino-1H-pyrazolo[3,4-d]pyrimidine 5 was obtained. The 6-hydrazinopyrimidines 6 could be converted into the pyrazolo[3,4-d], triazolo[4,3-c] and tetrazolo-[1,5-c]pyrimidines 7, 8 and 9 by the action of heating, trimethyl orthoformate and nitrous acid, respectively.
Pharmaceuticals, 2022
The Enterovirus genus includes many viruses that are pathogenic in humans, including Coxsackie vi... more The Enterovirus genus includes many viruses that are pathogenic in humans, including Coxsackie viruses and rhinoviruses, as well as the emerging enteroviruses D68 and A71. Currently, effective antiviral agents are not available for the treatment or prevention of enterovirus infections, which remain an important threat to public health. We recently identified a series of quinoxaline derivatives that were provento be potent inhibitors of coxsackievirus B5, the most common and a very important human pathogen belonging to the enterovirus genus. We have shown how most active derivatives interfere with the earliest stages of viral replication, blocking infection. Considering the broad antiviral spectrum, a very attractive property for an antiviral drug, we aimed to investigate the antiviral activity of the most promising compounds against other Enterovirus species. Here, we investigated the susceptibility of a panel of representatives of Enterovirus genus (enterovirus A71, belonging to A ...
European Journal of Medicinal Chemistry, 2018
Journal of Enzyme Inhibition and Medicinal Chemistry
Supporting Informations Figure S1. Superposition between: (A) The crystallographic pose of QK5 (c... more Supporting Informations Figure S1. Superposition between: (A) The crystallographic pose of QK5 (cyan sticks) and the lowest IFDScore binding prediction (pink sticks) (RMSD: 0.58). (B) The binding mode of Ibu-AM5 found after MDs [1] (violet sticks) and the best IFDScore solution found by the IFD protocol (green sticks) (RMSD: 1.34).
Metabolites
The tumor microenvironment is crucial for the growth of cancer cells, triggering particular bioch... more The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identifica...
Molecules
The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant... more The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by ...
Journal of Enzyme Inhibition and Medicinal Chemistry
Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by n... more Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by nonsteroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)À2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [ 3 H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a K i value of 0.26 mM and an a value of 4.9. At a concentration of 10 mM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
Proceedings of 4th International Electronic Conference on Medicinal Chemistry
Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysi... more Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysis of the fatty acid ethanolamide family of signaling lipids, which includes anandamide (AEA), an endogenous ligand for cannabinoid receptors. Endogenous FAAH substrates such as AEA serve key regulatory functions in the body and have been implicated in a variety of pathological conditions including pain, inflammation, sleep disorders, anxiety, depression, and vascular hypertension, and there has been an increasing interest in the development of inhibitors of this enzyme. Different structural classes of FAAH inhibitors have been reported including aketoheterocycles, (thio)hydantoins, piperidine/piperazine ureas, and carbamate derivatives. When tested, these compounds have been shown to be efficacious in models of inflammatory, visceral, and in some cases neuropathic pain without producing the central effects seen with directly acting cannabinoid receptor agonists. An intriguing aspect of FAAH inhibition is that some currently marketed nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to be weak inhibitors of FAAH, but can be used as a template for the design of more potent compounds. However, structure-activity relationships of analogues of clinically used NSAIDs with respect to FAAH inhibition have been examined scarcely in the literature. These findings led us to design and synthesis of new series of FAAH inhibitors derivable from conjugation of heterocyclic structures with NSAIDs as profens, fenamates, and new their correlate molecules. In this keynote we report on the synthetic pathways to transform old analgesic drugs into FAAH inhibitors and SAR studies on the new inhibitor series.
ChemInform
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Pathogens and Disease
Pyrrolyl heteroarylcarbothioamide derivatives are new dual inhibitors of both ribonuclease H and ... more Pyrrolyl heteroarylcarbothioamide derivatives are new dual inhibitors of both ribonuclease H and polymerase HIV-1 RT-associated functions, a new promising resource against drug resistance.