SYNTHESIS OF SYDNONES AND SYDNONE IMINES.
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Structure-optical property relationships in organometallic sydnones.
As part of an effort to develop a spectroscopic structure-property relationship in platinum acetylide oligomers, we have prepared a series of mesoionic bidentate Pt(PBu3)2L2 compounds containing sydnone groups. The ligand is the series o-Syd-(C6H4-C[triple bond]C)n-H, where n = 1-3, designated as Syd-PEn-H. The terminal oligomer unit consists of a sydnone group ortho to the acetylene carbon. We synthesized the platinum complex (Syd-PEn-Pt), the unmodified ligands (PEn-H), and the unmodified platinum complexes (PEn-Pt). The compounds were characterized by various methods, including X-ray diffraction, 13C NMR, ground-state absorption, fluorescence, phosphorescence, and laser flash photolysis. From solving the structure of Syd-PE1-Pt, we find the angle between the sydnone group and the phenyl group is 45 degrees . By comparison of the 13C NMR spectra of the sydnone-containing ligands, the sydnone complexes with the corresponding unmodified ligands and complexes not containing the sydnone group, the sydnone group is shown to polarize the nearest acetylenes and have a charge-transfer interaction with the platinum center. Ground-state absorption spectra of the complexes in various solvents give evidence that the Syd-PE1-Pt complex has an excited state less polar than the ground state, while the PE1-Pt complex has an excited state more polar than the ground state. In all the higher complexes the excited state is more polar than the ground state. The phosphorescence spectrum of the Syd-PE1-Pt complex has an intense vibronic progression distinctly different from the PE1-Pt complex. The sydnone effect is small in Syd-PE2-Pt and negligible in Syd-PE3-Pt. From absorption and emission spectra, we measured the singlet-state energy E(S), the triplet-state energy E(T), and the singlet-triplet splitting Delta E(ST). By comparison with energies obtained from the unmodified complexes, attachment of the sydnone lowers E(S) by approximately 0.1 eV and raises E(T) by approximately 0.1 eV. As a result, the sydnone group lowers Delta E(ST) by approximately 0.2 eV. The trends suggest one of the triplet-state singly occupied molecular orbitals (SOMOs) is localized on the sydnone group, while the other SOMO resides on the rest of the ligand.
Journal Article↗
Sydnone derivatives: synthesis and antimicrobial activity.
Amongst a number of mesoionic compounds studied so far, sydnones have attained importance due not only to their structural features and chemical properties, but also to their biological properties. Sydnone derivatives have been extensively studied for their biological activities, the antimicrobial activity of substituted aryl sydnones has been reported. Aryl sydnones are less toxic and more active than alkyl sydnones. Also chalcone analogues are known to have antimicrobial activity.
Anti-Bacterial Agents↗
Synthesis and antimicrobial activity of 3-(substituted-phenyl)-sydnones.
3-(3 or 4-Acetylphenyl)-sydnones 7, 8 have been synthesized by formation of the glycines 3, 4, followed by nitrosation to 5, 6 and cyclization with acetic anhydride to sydnones. Sydnone derivatives carrying chalcone moieties 15, 16 were prepared by formation of the chalcone analogues 11, 12 through condensation of the glycines 3, 4 with the appropriate aldehydes, followed by the reactions applied for the preparation of 7, 8. The sydnone derivatives were screened for antimicrobial activities.
Anti-Bacterial Agents↗
Evidence for mechanism-based inactivation of rat and chick embryo hepatic cytochrome P4501A and P4503A by dihydropyridines, sydnones, and dihydroquinolines.
Rat hepatic P4501A1 and 3A1/2 have been shown previously to be targets for mechanism-based inactivation by the 4-alkyl analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), namely, 4-ethyl DDC and 4-isopropyl DDC. In this study we have shown that rat hepatic P4501A and P4503A are targets for mechanism-based inactivation by the sydnones, 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) and 3-(2-phenylethyl)-4-methylsydnone (PEMS). The dihydroquinoline, 2,4-diethyl-2-methyl-1,2-dihydroquinoline (DMDQ), caused mechanism-based inactivation of rat hepatic P4501A but not of P4503A. The P4501A isozyme(s) of chick embryo liver was found to share the ability of rat liver P4501A to serve as a target for mechanism-based inactivation by the dihydropyridines, 4-ethyl DDC and 4-isopropyl DDC, the sydnones, TTMS and PEMS, and the dihydroquinoline, DMDQ. A P4503A-like isozyme of chick embryo liver shared the ability of the rat liver P4503A isozyme(s) to serve as a target for mechanism-based inactivation by the dihydropyridines, 4-ethyl DDC and 4-isopropyl DDC, and the sydnone, TTMS, but not of the sydnone PEMS. The dihydropyridine, DDC, was found to serve as a mechanism-based inactivator of the chick embryo P4501A isozyme(s), but not of the P4503A isozyme(s), in contrast to its previously reported inactivity with both the rat hepatic P4501A1 and 3A1/2 isozymes.
Animals↗
New NO-donors with antithrombotic activities and vasodilating activities, III: 3,4-disubstituted N-nitroso-5-sydnone imines.
38 title compounds have been synthesized. They bear a wide variety in substituents including alkyl-, aryl-, arylalkyl-, and styryl groups. The anti-platelet activities elucidated in the Born-test with collagen cover more than two orders of magnitude (IC50 = 0.3-45 mumol/L). These effects depend on the presence of the N-NO-group. This is shown by comparison with the corresponding sydnone imines, sydnone cyanimines, and sydnones. The most suitable substituents were phenylethyl, styryl, and hexyl at either position of the molecule. Seven compounds, most of them styryl derivatives, have IC50 values below 1 mumol/L. It is suggested that the differences in activity are connected with the ability of the compounds to bind to the platelet membrane.
Animals↗
Synthesis and biological testing of novel analogues of sydnone as potential antibacterial agents.
Several series of 3-phenylsydnone derivatives conjugated to well-known moieties with antibacterial activity were synthesized via several routes. These derivatives include 3-cyano-2-oxopyridine, 2-amino-3-cyanopyridine, 2-arylidene-1-ethylidenehydrazine and 2-aroyl-1-ethylidenehydrazine moieties. Thus, the key intermediate 3-(4-acetylphenyl)sydnone (3) was allowed to react with the appropriate aldehyde, ethyl cyanoacetate or malononitrile in presence of excess ammonium acetate in two steps (method 1) or through a one-pot reaction technique (methods 2 and 3) to give the corresponding sydnone derivatives 5 and 6, respectively. Moreover, condensation of compound 3 with hydrazine hydrate followed by the reaction with the appropriate aldehyde, mono- and dicarboxylic acid hydrazide yielded the corresponding sydnone derivatives 8, 9 and 10, respectively. Most of the synthesized compounds were screened for their in vitro antibacterial activity against various pathogenic organisms of both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentrations (MICs) were determined using agar dilution method.
Anti-Infective Agents↗
Novel analogues of sydnone: synthesis, characterization and antibacterial evaluation.
New sydnone derivatives bearing a substituted phenyl ring at the 3-position have been synthesized. Two separate series of 3-(carboxyphenyl)sydnone derivatives have been prepared by cyclization of the corresponding N-nitroso-N-(carboxyphenyl)-glycine 3. The obtained 3-(carboxyphenyl)sydnones 4 were subjected to a series of different chemical reactions on the carboxylic acid group. Compound 5, the potassium salt of 4a, was reacted with alpha-chloroacetanilide derivatives 6 to give the corresponding esters 7. On the other hand, the acid hydrazide 9 was condensed with different aromatic aldehydes to give the corresponding arylidene derivatives 10. The synthesized compounds were tested for their antibacterial activities against both gram-positive and gram-negative organisms. Some of the test compounds exhibited high activity; among them, 10d is considered to be a lead compound possessing high broad-spectrum antibacterial activity.
Anti-Bacterial Agents↗
Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XX: 4,4',4''-(1,3,5)-benzene-tris-sydnone imines.
The synthesis of ten tris-sydnone imine derivatives, unknown up to now, is described. All compounds are alkyl or arylalkyl substituted in 3-position of the sydnone imine. The most powerful agent was the 3-propyl derivative 6c. It inhibits the aggregation of human platelets induced by collagen in a concentration of 1 mumol/L half maximally. Its N-ethoxycarbonyl derivative 7c, which was designed as a prodrug, showed only small antithrombotic effects in rats. The reason for this low degree of activity is discussed.
Animals↗
Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XXI: 4,4'-Alkylene-bis-sydnone imines.
Two methylene-, seven ethylene-, eleven propylene- and two 4,4'-butylene-bis-sydnone imines have been synthesized and tested for their antiplatelet (Born-test, collagen) and anticoagulant (Quick-test) activity in vitro. The most active compounds were found in the ethylene and propylene series. The most favourable substituents in 3-position of the sydnone were hexyl to octyl or phenylethyl to phenylbutyl groups. Six compounds exhibit an IC50 < or = 10 mumol/L against platelet aggregation. Three compounds showed an IC75 < or = 200 mumol/L concerning the fibrin formation (Quick delta t > or = 7 s).
Anticoagulants↗
New NO-donors with antithrombotic and vasodilating activities, I: 3-Arylalkyl-N-nitroso-5-sydnone imines.
Nine nitrosimino title compounds were prepared. They inhibit the aggregation of human platelets induced by collagen with an IC50 = 0.7--33 mumol/L. The most active substance is the 3-phenylethyl derivative 6b. The in vitro effect is mediated by an active metabolite which is formed by a photochemical reaction in the aggregometer. As the corresponding and so far unknown sydnone-5-cyanimines have no effect on platelets the metabolite is most certainly a NO-species. The activity of the sydnone-5-nitrimine 5b is in the same order of magnitude (IC50 = 7.5 mumol/L) as in the nitrosimines of type 6. The most active compound 6b was investigated for antithrombotic properties in a thrombosis model, where the thrombus formation was induced by a laser-beam. 2 h after oral administration of 60 mg/kg of 6b to rats in venoles a 28% inhibition of thrombin formation was found. In arterioles this effect is more evident and a 48% inhibition is seen (the thrombus formation index is 2.6 and 3.9, respectively). These results suggest that the active metabolite is formed as well in vivo.
Fibrinolytic Agents↗
New NO-donors with antithrombotic and vasodilating activities, II: 3-alkyl-N-nitroso-5-sydnone imines.
Fifteen 3-alkyl-, four 3-cycloalkyl-N-nitroso-5-sydnone imines and five 3-alkyl-N-nitro-5-sydnone imines were synthesized and their ability to inhibit platelet aggregation induced by collagen (Born-test) was studied in vitro. Dependent on the chemical structure, the IC50-values for the inhibition of platelet aggregation were in the range of 0.2-140 mumol/L. It is suggested that this scale reflects different binding properties of the nitrosimines with respect to the platelet membrane. Highest activities were observed for the 3-hexyl (2f) and the 3-cyclohexyl (2p) derivative. Three nitrimines (3e, 3f, 3i) also showed IC50 values below 10 mumol/L. For the nitrosimines 2a, 2f, and 2m antithrombotic activity was demonstrated in vivo. They inhibited laser induced arterial thrombosis in anesthetized rats up to 70% two h after oral administration. In conscious renal-hypertensive dogs, the decrease in systolic blood pressure and left ventricular enddiastolic pressure suggests an antianginal activity of the compound 2a similar to that of molsidomine (M). The smoother onset and the longer duration of action of the new compound as compared to M could be a significant advantage of 2a in the therapy of angina pectoris.
Animals↗
New NO-donors with antithrombotic and vasodilating activities, V: Oligonitroso sydnone imines.
Nine 4,4'-bis- and four 4,4'-tris-N-nitroso syndrome imines were synthesized. The sydnone imine moiety is connected either by aromatic 1,3-phenylene or 1,3,5-benzene or aliphatic methylene or propylene bridges. Compared to the corresponding sydnone imines the collagen induced platelet aggregation inhibiting activity is increased by several orders of magnitude by the nitroso derivatives. The most potent compound bears a hexyl substituent in 3-position (1d: IC50 = 0.05 mumol/L). These data show that aromatic bridges (1d, 2d) are more favourable than aliphatic ones (4b). This indicates the mutual influence of the nitroso-imino moieties via the aromatic bridges. In the series of 3,3'-bis-nitrososydnone imines (13 compounds) mostly additive effects of the nitroso groups are seen. The activities range from IC50 = 0.2 mumol/L (5i; 1,3-xylene bridge) to IC50 = 8 mumol/L (5b; trimethylene bridge). The differences suggest different affinities to the platelet membrane.
Animals↗
Synthesis and biological evaluation of a novel phenyl substituted sydnone series as potential antitumor agents.
A series of compounds containing an N-(4'-substituted-3'-nitrophenyl)sydnone moiety with potential antitumor activity was prepared based on active analogues. The rationale behind the design of these compounds is presented along with the 4-step synthetic route to the derivatives in the 4'-position of the phenyl sydnone framework. Out of the six novel compounds, the 4'-fluoro derivative has an improved activity against all three cell lines as compared to the earlier leads.
Antineoplastic Agents↗
Synthesis, metabolism, and disposition of the antiinflammatory 3-[2-(4-methylphenyl)-thioethyl]-sydnone-5-14C in the rat.
The synthesis, as well as the in vivo and in vitro disposition, of 3-[2-(4-methylphenyl)thioethyl]-sydnone-5-14C (5) in the rat is described. After intraperitoneal injection of a single dose of 5 in female Sprague-Dawley rats, the distribution and excretion of radioactive substances was monitored (24 h). Radioactivity in the blood declined in a biphasic manner with half-lives of 0.55 and 15.2 h for the alpha- and beta-phase, respectively. About 8% of the administered radioactivity was detected in feces and approximately 90% in urine (24 h). In 3.75 h, 50% of the radio-dose was excreted in the urine. Tissue distribution studies demonstrated a selective uptake of radioactivity only by the adrenal glands and the ovaries. The radioactivity in these organs reached a maximum approximately 1 h after dosing and then declined rapidly. None of the parent drug was excreted from such a single dose (i.p. injection) which indicated rapid in vivo metabolism. Nor could there be found any metabolites related to the whole structure, for example, the sulfoxide or aromatic hydroxy compounds. The sydnone 5, its sulfoxide and unconjugated metabolites were detected and quantitated by GC/MS methodology using unlabelled authentic samples. Radioactive carbon dioxide was not detected during the in vivo or in vitro experiments, nor was it released from alkaline urine samples upon acidification. Radiolabelled urinary metabolites were glycolic acid-1-14C 9 (34%), its glycine conjugate 10 (52%) and 3-vinylsydnone-5-14C 11 (4%).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Platelet aggregation inhibiting and anticoagulant effects of oligoamines, XIX: 4,4'-Phenylene-bis-sydnone imines.
Fourteen 4,4'-m-phenylene- and two 4,4'-p-phenylene-bis-sydnone imine hydrochlorides have been synthesized. All compounds exhibited good solubility in water. In the m-series the 3-(3-phenylpropyl)-derivative 5c and the 3-hexyl compound 5l showed antiplatelet activities at or below 10 mumol/L (IC50, Born-test with collagen). The corresponding p-compounds had the same (6l) or slightly lower (6c) activity. No effect on the fibrin formation (Quick-test) could be observed.
Anticoagulants↗
Synthesis and antiinflammatory, analgesic, and antipyretic testing of 4-[1-oxo-(3-substituted aryl)-2-propenyl]-3-phenylsydnones and of 3-[4-[3-(substituted aryl)-1-oxo-2-propenyl]phenyl]sydnones.
Two series of styrylcarbonyl 3-phenylsydnone derivatives, 4-[1-oxo-(3-substituted aryl)-2-propenyl]-3-phenylsydnones (series 1, 1-21) and 3-[4-[3-(substituted aryl)-1-oxo-2-propenyl]phenyl]sydnones (series II, 22-40), were synthesized and evaluated pharmacologically at a dose of 100 mg/kg po. Eleven compounds in series I plus one in series II and six in series I plus seven in series II were active in the carrageenan-induced edema and acetic acid-induced writhing assays, respectively. Compound 35 in the latter assay showed activity somewhat similar to that of the positive control drug, aspirin, administered at the same dosage. Compounds 11, 17, and 23 showed activity in both assays, and 23 also was active in the adjuvant-induced arthritis assay.
Acetates↗
Complete 1H and 13C NMR spectral assignment of cis- and trans- 3-(2-[2-(4-methylphenyl)ethenyl]phenyl])sydnones.
1H and 13C NMR spectra of cis- and trans-3-(2-[2-(4-methylphenyl)ethenyl]phenyl])sydnones, the first stilbene-substituted mezoionic oxadiazolium rings, were fully assigned combining the information in various solvents, such as deuterated benzene, acetone and chloroform, using 2D NMR techniques.
Acetone↗