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Antiprotozoal activity of novel diaryliminophenazines
Full text linkRecently, we synthesized a set of novel iminofenazines bearing a bicyclic basic head linked through an alkyl chain to the imino nitrogen in position 3 on the phenazine nucleus (Fig.1).
Most of these compounds inhibited the growth of different species of Leishmania promastigotes as well as of chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of P. falciparum with IC50 in the submicromolar range. Unfortunately, these compounds exhibited also a significant toxicity against the human endothelial cell line HMEC-1 with IC50 in the low micromolar range and with a consequent low selectivity index.
Figure1.Structures of the previously synthesized compounds.
To continue the studies on the antiprotozoal potentialities of this class of compounds and with the aim to improve their activity and selectivity on protozoa, we have now synthesized novel compounds characterized by the replacement of the aniline moiety in pos. 2 of the phenazine nucleus with an aminopyridine, and/or by a quaternarization of the basic nitrogen in the side chain with a methyl group (Fig.2).
Figure 2. Structures of the new compounds synthesized.
The in vitro activity of the new compounds on Leishmania promastigotes and on CQ-S and CQ-R strains of P. falciparum, as well as on the HMEC-1 cell line will be presented and discussed.
References
[1] A. Barteselli, M. Gavazzi, N. Basilico, S. Parapini, D. Taramelli, A. Sparatore. Clofazimine analogs with antileishmanial and antimalarial activities. XXII National Meeting on Medicinal Chemistry, Roma 2013
Acido acetilsalicilico a rilascio di idrogeno solforato : effetti farmacologici
No full textLa recente scoperta del ruolo biologico dell’idrogeno solforato ha portato ad ipotizzare un potenziale uso terapeutico di questo gas in patologie caratterizzate da una componente infiammatoria e/o da aumentato stress ossidativo. A questo scopo, particolarmente utili sembrano essere molecole in grado di rilasciare in vivo H2S in modo controllato e risultati particolarmente interessanti sono stati riportati nell’utilizzo di ibridi di farmaci noti con molecole donatrici di questo gas.
Tra questi, particolarmente interessante è risultato essere l’estere dell’acido acetilsalicilico con il 5-(4-idrossifenil-1,2-ditiol-3-tione), ACS14, un derivato dell’aspirina in grado di rilasciare in vivo, in seguito ad attivazione metabolica, piccole quantità di idrogeno solforato.
Dai numerosi studi preclinici effettuati è emerso che ACS14 mantiene l’attività trombossano soppressiva dell’aspirina, senza i ben noti effetti gastrolesivi del farmaco, contrastando gli squilibri ossido riduttivi attraverso l’aumento di H2S circolante e la formazione di glutatione, oltre ad un’azione promotrice la formazione di eme ossigenasi-1 (HO-1) e alla soppressione degli isoprostani. E’ stata anche osservata una significativa riduzione dei livelli di omocisteina nella maggior parte degli organi e nel plasma di ratti trattati con questo composto.
Inoltre, ACS14 esercita un forte effetto antiaggregante piastrinico attraverso vari meccanismi, riduce il danno da stress ossidativo in ratti trattati con BSO e limita significativamente la disfunzione endoteliale vascolare nel tessuto aortico, la relativa ipertensione e infiammazione e il danno miocardico in esperimenti di ischemia /riperfusione.
Dai dati sperimentali attualmente disponibili, ACS14 sembra quindi essere un composto efficace e sicuro, con significativi vantaggi rispetto al “parent compound” aspirina.
Il profilo farmacologico di ACS14 appare utile e promettente per il trattamento di patologie aventi una base infiammatoria, come le patologie cardiovascolari e la sindrome metabolica, ma anche patologie neurodegenerative come il morbo di Alzheimer
COMPOUNDS FOR TREATING METABOLIC SYNDROME
No full textCompounds of general formula: wherein R', R, x and z have the meaning reported in the specification, are useful for treating inflammatory diseases including metabolic syndrome, diabetes, obesity, dyslipidemia, and insulin resistance
[Quinolizidinyl derivatives of tricyclic systems]
No full textSince the pharmacological screening of several lupinyl- and lu lupinyldene derivatives of three-ring systems showed several interesting activities on the C.N.S., new investigations have been undertaken in order to understand the neurochemical mechanisms underlying such activities (influence on the uptake of choline, norepinephrine and serotonin by isolated rat brain synaptosomes). Thus the series of lupinyl derivatives has been completed with N-lupinyl-2-chloroiminodibenzyl and N-lupinyl-2,3-hexamethyleneindole; moreover, for all the three-ring systems so far considered, the corresponding epi-lupinyl- and epi-lupinylidenderivatives have been prepared in order to check the significance of the steric relationships between the quinolizidine ring and the tricyclic systems. The latter compounds differ from those formerly described for the equatorial position (rather than axial) of the methylene or methine group joining the quinolizidine nucleus to the three-ring systems
New rosmaricine derivates as anticancer agents
No full textRosmaricine (Fig.1) is a diterpenoid aminocompound obtained from dried leaves of Rosmarinus officinalis L. treated with ammonia in the presence of air. It is an alkaloidal artifact formed through a complex reaction between some oxidation derivatives of carnosic acid and the ammonia used to liberate the bases supposed to be present in the ethanolic extract.1,2
Rosmaricine is structurally similar to the natural diterpenes carnosol and rosmanol, both endowed with antioxidant, radical scavenger and antiproliferative activities through a mechanism that involve, among others, NF-kB and STAT-3 inhibition.3
In view of the growing interest on terpenoid compounds as potential antitumoral drugs and following our recent studies on sulphurated drug-hybrids as multitarget anticancer agents,4,5 we synthesized three new derivatives through the condensation of the amino group of rosmaricine with some sulfurated carboxylic acids, containing a thiosulfonate or allyldisulfide or a dithiolethione moiety (Fig. 1) and investigated their ability to inhibit STAT-3 and NF-kB transcription factors as well as their antiproliferative activity on a human cancer cell line.
Results showed that rosmaricin and its derivatives inhibited HCT-116 cell proliferation in vitro with IC50 in micromolar range. In addition, they were able to strongly and selectively bind STAT-3 SH2 domain in an Alpha Screen assay and were also able to inhibit the NF-kB transcriptional activity in HCT-116 cell line.
The obtained data underline the interesting profile of these compounds which are worthy of further investigation as potential multitarget anticancer agents.
References
1. E. Wenkert, A. Fuchs, J.D. McChesney J.Org. Chem. 1965, 30, 2931-2934.
2. A. Boido, F. Savelli, F. Sparatore Il Farmaco 1994, 49, 111-114.
3. C. Lai, J. H. Lee, C. Ho, C. B. Liu, J. Wang, J. Wang, M. Pan J. Agric. Food Chem. 2009, 57, 10990-10998.
4. Gabriele E.; Barteselli A.; Moiana V.; Porta F.; Gelain A.; Asai A.; Sparatore A. Methanethiosulfonate derivatives as ligands of STAT3-SH2 domain. “Tefarco NFPC8” (Parma, Italy, 9-11 June 2014); Poster communication P-18.
5. Gabriele E.; Brambilla D.; Ferri N.; Asai A.; Sparatore A. New sulfurated cinnamic acid derivative as multitarget anticancer agents. Book of Abstract – SIMCC2015 - Spanish-Italian Medicinal Chemistry Congress (Barcellona, Spain - July 12-15, 2015) - P-90
Preparation and pharmacological activities of homolupinanoyl anilides
No full textOn the pattern of well known dialkylaminoacyl anilides, a set of N-homolupinanoyl anilides was prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. As expected most compounds exhibited a strong antiarrhythmic activity, often comparable or superior to that of lidocaine and quinidine. Compound 1 exhibited an unusual profile as antiarrhythmic, being devoid of local anesthetic activity, calcium channel and beta adrenoceptor antagonism. Calcium channel blocking activity was seen in all aminobenzophenone derivatives, but not in the simpler anilides. Noteworthy are also the capacity of compound 7 to protect mice from a lethal dose of KCN, the moderate antihypertensive activity of 10 and, above all, the antagonism to guinea pig ileum contractile responses induced by several agents exhibited by compound 11, which deserves further investigation for a potential use in irritable bowel syndrome. Compound 11 showed also good relaxant activity on tracheal strips and inhibitory activity against arachidonate induced platelet aggregation. Finally, compound 11 displaced several radioligands from their respective binding sites. Most potent was displacement of [3H]pirenzepine (IC50 < or = 0.01 microM) from M1 binding sites of rat brain, while displacement of [3H] methylscopolamine from rat heart (M2) and submaxillary salivary glands (M3) preparations was much weaker (IC50 approximately equal to 2.4 and 1.3 microM, respectively)
2-{4-[ω-[4-(2-methoxyphenyl)-1-piperazinyl]alkoxy]phenyl}-2H-benzotriazole s and their N-oxides as ligands for some 5-hydroxytryptamine, dopamine and adrenergic receptor subtypes
No full textWe have prepared and studied some new 2-methoxyphenylpiperazine derivatives as combined ligands for 5-hydroxytryptamine 5-HT(1A) and dopamine D3 receptor subtypes. The compounds displayed affinity for 5-HT(1A) and D3 receptors, which improved with the lengthening of the intermediate aliphatic chain. Conversely, binding to 5-HT(2A), D2 and α1-receptor subtypes was affected in an irregular, and mainly negative, manner by the chain length. Benzotriazole derivatives with 4-5 methylenes exhibited good or excellent selectivity for 5-HT(1A) and D3 vs 5-HT(2A), D2 and α1-receptors
Preparation and pharmacological activities of 10-homolupinanoyl-2-R-phenothiazines
No full textPursuing our researches on quinolizidinyl derivatives of phenothiazine and on the ground of antidepressive, diuretic, antianginal and antiarrhythmic activities of several 10-(3-dialkylamino) propionylphenothiazines (as chloracizine, moricizine, etc.), six 10-homolupinanoyl-2-R-phenothiazines were prepared and subjected to a broad pharmacological screening with in vivo and in vitro assays. Most of these compounds exerted strong antiarrhythmic activity (compounds 1, 3 and 5 were comparable or superior to lidocaine and quinidine in three tests), calcium antagonism on guinea pig ileum and left atria, antagonism to smooth muscle contractile responses induced by several agents and inhibition of rabbit platelet aggregation induced by PAF and ADP. A few other activities were characteristic of single compounds, as antagonism to central and peripheral effects of oxotremorine 1, moderate antihypertensive activity 5, local anesthetic activity and antagonism to substance P 2, antiinflammatory activity with low or absent gastric irritation 2, 3, powerful saluretic action 6, inhibition of arachidonate induced platelet aggregation 1 and antagonism to PAF induced mortality 1, 4. The last activity is very unusual and deserves further investigation. The capacity of compound 1 to displace specific ligands from several receptors was also investigated. Significant binding for M1 (IC50 = 0.03 microM), M3 (IC50 = 10 microM), sigma receptors and Na+ channels (IC50 = 1 microM) were evidentiated
2-{4-[ω-[4-(2-methoxyphenyl)-1-piperazinyl] alkoxy] phenyl}phthalimides as ligands for some 5-HT, dopamine and adrenergic receptor subtypes
No full textWe have prepared and studied some new 2-methoxyphenylpiperazine derivatives as combined ligands for 5-HT1A and D3 receptor subtypes. The introduction of a phenyloxy moiety between the phthalimido group and the polymethylene chain of nanserone does not impair the typical high affinity for 5-HT1A receptors, but reduces in different measures the affinity for 5-HT2, D2 and α1-receptors. Good affinity for the D3-receptor subtype has also been observed. The polymethylene chain length remains a critical factor in determining optimal affinity and selectivity
Sulindac Derivatives for Treatment of Cancer
No full textThe present invention relates to novel non steroidal anti-inflammatory compounds (NSAIDs) derivatives of sulindac, for the treatment/prevention, alone or in combination, of cancer
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