Synthesis and pharmacological activity evaluation of curcumin derivatives

Curcumin 3,4-dihydropyrimidinones/thiones/imines have been synthesized using one-pot cyclocondensation of curcumin with substituted aromatic aldehydes and urea/thiourea/guanidine in the presence of chitosamine hydrochloride as a biodegradable and nontoxic catalyst under solvent-free microwave irradiation. The synthesized product was purified by crystallization from ethanol and the process does not involve any hazardous solvent. All the synthesized curcumin derivatives 4a-o were screened for antioxidant and anti-inflammatory activity. Biological activity data of the synthesized showed that most of the synthesized compounds exhibited greater antioxidant and anti-inflammatory activity than curcumin.     

Synthesis of some furochromonesulfonamide derivatives with potential pharmacological activity

A number of visnagin-9-sulfonamides 1-3 have been prepared. In two instances side-products have been isolated in which the γ-pyrone ring is opened. All compounds were characterized by high-field ¹H and ¹³C nmr and mass spectra.     

Synthesis and pharmacological activity of sulfate conjugates at 6-position of N-substituted normorphine derivatives.

Three pairs of N-substituted normorphine derivatives and the sulfate conjugates at the 6-position were tested for the analgesic and antagonistic activities and the development of physical dependence in mice. The compounds examined were nalorphine, nalorphine-6-sulfate (N-6-S), N-cyclopropylmethylnormorphine (CPN), N-cyclopropylmethylnormorphine-6-sulfate (C-6-S), N-dimethylallylnormorphine (DMN) and N-dimethylallylnormorphine-6-sulfate (D-6-S). The latter two pairs were newly synthesized. The analgesic activity of C-6-S and D-6-S was equipotent to that of CPN and DMN by the acetic acid writhing test on the s.c. injection, and the activity of N-6-S was about 2 times more potent than that of nalorphine. The antagonistic activity of N-6-S, C-6-S and D-6-S to morphine analgesia was higher than that of the parent compounds by the tail pinch test on i.c.v. injection. A withdrawal sign was seen in mice treated chronically with CPN, C-6-S and N-6-S by challenge with naloxone, whereas the mice treated with DMN, D-6-S and nalorphine showed no such sign. The effect of sulfation at the 6-position on the development of physical dependence was not well associated with the effect on agonistic and antagonistic activities.     

Synthesis and pharmacological evaluation of pyrroloazepine derivatives as potent antihypertensive agents with antiplatelet aggregation activity

A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthesized and evaluated as alpha 1 adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potently exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)piperidino]butyl group at the 1-position exhibited both activities, and varied significantly in terms of the substituents at the 4-position of the pyrroloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7- methyl-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha 1-adrenergic antagonistic activity (pA2 = 8.89 +/- 0.21) and 5-HT2 antagonistic activity (pA2 = 8.74 +/- 0.22) in isolated guinea pig arteries. This compound exhibited antihypertensive activity and a duration of action equivalent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spontaneously hypertensive rats, as well as potent antiplatelet aggregation activity.     

Synthesis of novel phthalazine derivatives as pharmacological activities

Phthalazine derivatives attached to amino acid derivatives were synthesized with high yields. The reaction of phthalazine derivatives with different phthalyl and tosylamino acids such as glycine, alanine, phenylalanine, valine, serine, and threonine in the presence of N,N-dicyclo hexylcarbodiimide (DCC) as a dehydrating agent reagent yielded high yields of the afforded compounds. Phthalylamino acids derivatives were obtained by deprotection of phthalazine derivatives, with the latter heating with hydrazine hydrate. The chemical structures of all phthalazine derivatives were affirmed by elemental analysis and spectral data (IR, MS, ¹HNMR, and ¹³C NMR). Screening out and estimation of the synthesized derivatives for their cytotoxic and antioxidant activity were done, and most of them showed powerful activity in comparison with standard drugs.     

Synthesis of new thiazolidine and imidazolidine derivatives of pharmacological interest

The hitherto unknown 5‐(2‐aryl‐2‐oxoethyl)‐4‐oxo‐1,3‐thiazolidines 1a‐l have been synthesized viacycloaddition process between thiourea and/or its derivatives with 3‐aroylpropenoic acids. ¹H NMR spectra revealed the presence of 1a‐c as a tautmeric mixture. The presence of the thiazoline tautmers (1a‐c) ′ was confirmed by methylating the tautmeric mixture, to the respective methylated derivatives 2‐N‐methylanilino‐5‐(2‐aryl‐2‐oxoethyl)‐4‐oxo‐1,3‐thiazolines 2a‐c and 1g‐i . Acidic treatment of 1 provided the respective 2‐oxo homologues 3a‐i . When 1a‐d , k were refluxed with DMF, molecular rearrangement was achieved, providing the 4‐oxo‐2‐thioxoimidazolidine isomers 4a‐d , k . Bromination of 4a and 4d in hot acetic acid afforded the respective (E,Z)‐5‐benzoylmethylene derivatives 5a,d which were prepared authentically. Thiation of 1a‐c and 4a‐c gave 5‐aryl‐2,3‐dihydro‐2‐phenyliminothieno[2,3‐d]thiazoles 6a‐c and 1‐phenyl‐5‐aryl‐2,3‐dihydro‐2‐thioxothieno[2,3‐d]imidazoles 7a‐c , respectively. The proposed structures have been confirmed by elemental analysis and spectroscopic data. The selected products showed different antimicrobial effect.     

Synthesis and pharmacological evaluation of new 16-methyl pregnane derivatives

The pharmacological activity of several new pregnane derivatives 15-19 were determined on gonadectomized male hamster flank organs, seminal vesicles and in vitro conversion of testosterone (T) to dihydrotestosterone (DHT) as 5alpha-reductase inhibitors. Steroids 15-19 decreased the diameter of the pigmented spot in the flank organs as compared to the T treated animals; in this model, steroids 16 and 19 showed a higher activity than the commercially available finasteride 3. Injection of T increased the weight of the seminal vesicles. Compounds 15-19 when injected together with T decreased the weight of the seminal vesicles thus showing an antiandrogenic effect. The trienone 19 exhibited a considerably higher activity than finasteride. Steroids 15-19 inhibited the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. Compounds 18 and 19 showed a much higher antiandrogenic effect than finasteride. This enhancement of the biological activity could probably be attributed to the coplanarity of the steroidal skeleton as previously observed by our group. The high antiandrogenic activity of the epoxy compound 16 is probably the result of the ring opening of the oxiran ring with the nucleophilic part of the enzyme 5alpha-reductase thus leading to a stable adduct with concomitant deactivation of this enzyme.     

Synthesis and pharmacological evaluation in mice of halogenated cannabidiol derivatives

Six halogenated derivatives of cannabidiol (CBD, 1) substituted on the aromatic ring at the 3' and/or 5' position, 3'-chloro- (2), 3',5'-dichloro- (3), 3'-bromo- (4), 3',5'-dibromo- (5), 3'-iodo- (6) and 3',5'-diiodo-CBD (7) were synthesized and their pharmacological effects of barbiturate-induced sleep prolongation, anticonvulsant effects and locomotor activity were evaluated by intravenous (i.v.) injection in mice. 2 (10 mg/kg, i.v., 69 +/- 10 min) significantly prolonged pentobarbital-induced sleeping time by 3.1-fold, compared to control (22 +/- 2 min), although other 1 derivatives used did not significantly affect the sleeping time. 2, 4 and 6 (10 mg/kg, i.v.) significantly prolonged hexobarbital-induced sleeping time by 2.0-, 2.0- and 2.3-fold, respectively, compared with control (52 +/- 5 min). On the other hand, 1 and all halogenated derivatives did not significantly prolong barbital-induced sleeping time. The monohalogenated derivatives, 2, 4 and 6 were able to prolong pentobarbital and hexobarbital-induced sleeping time, although the dihalogenated derivatives, 3, 5 and 7 did not exhibit a prolongation of the sleeping time. All halogenated derivatives of 1 except for brominated derivatives (2, 3, 6, 7) tended to prolong tonic seizure latency induced by pentylenetetrazol. 1 and its halogenated derivatives did not exhibit any prolongation of seizure latency induced by picrotoxin or strychnine. Maximal electroshock test demonstrated that 1 and 4 exhibited almost the same potency in their anticonvulsant effects, although other 1 derivatives 2, 3, 5, 6 and 7 did not show significant effect up to a dose of 63 mg/kg, i.v. The ED50 values (mg/kg, i.v.) of 1 and 4 were 38 and 44, respectively. 1 and 4 also showed anticonvulsant effect in minimal and maximal electroshock-threshold tests. 2, 4 and 6 tended to decrease the total distance (horizontal activity) and number of rearings (vertical activity) of mice, whereas 3, 5 and 7 tended to increase the number of rearings. However, the effects of all derivatives were not statistically significant from the control. 2 and 4 were the most potent derivatives on pharmacological activities among the synthetic cannabinoids examined in the present study. These results indicate that monohalogenation of 1 leads to some modification of the pharmacological profile of CBD.     

Synthesis and pharmacological activity of silyl isoxazolines 2

Silyl isoxazolines have been synthesized by [2+3] cycloaddition reaction of nitrile oxides to vinyl- and allylsilanes. The addition of 3-pyridylnitrile oxide to 1,3-divinyl-1,1,3,3-tetraphenyldisiloxane affords 1,3-bis{5-[3-(3-pyridyl)isoxazolin-2-yl]}-1,1,3,3-tetraphenyldisiloxane; the latter exists as a mixture of trans- and cis-isomers.The bond angle of the Si–O–Si fragment in thetrans-isomer equals 180(3)° and in the cis-isomer it is 162(3)°.The pharmacological properties of 4-[3-(5-trimethylsilylisoxazolin-2-yl)]pyridinium-chloride have been studied.     

Synthesis,characterization, pharmacological,molecular modeling and antimicrobial activity evaluation of novel isomer quinoline derivatives

The structural and spectroscopic characteristics of the synthesized structurally novel compound 4-chloro-6-methylquinoline-2(1H)-one (4C6MQ) and its isomer 4-chloro-8-methylquinoline-2(1H)-one (4C8MQ) have been examined by means of experimental and computational quantum chemical methods like density functional theory (DFT). The crystal structure of the 4C6MQ compound has been brought to light by single-crystal x-ray diffraction (SCXRD) method which consists of two independent molecules (A and B) in the asymmetric unit with similar conformations. Both the isomer compounds are characterized spectroscopically by FTIR, FT-Raman, UV-Vis, and NMR spectrum and compared with DFT results. The geometries of the isomer compounds have been optimized by using DFT/B3LYP method with the 6-311G++(d,p) basis sets. From the optimized geometry of the compounds, geometric parameters (bond lengths, bond angles, and torsion angles); vibrational analysis; chemical shifts; and electronic absorption of the isomer compounds have been computed and compared with the experimental result. The detailed assignments of vibrational wave numbers have been prepared based on potential energy distribution (PED) which was carried out in the VEDA4 program. In addition, natural bonding orbital analysis, frontier molecular orbital, and molecular electrostatic potential have been explained theoretically. The in silico (absorption, distribution, metabolism, excretion and toxicity) studies were analyzed to identify the potential drug likeliness of the isomer compounds. The implications of the inhibitory activity of isomer compounds against DNA gyrase and lanosterol 14 α-demethylase enzyme by molecular docking are discussed. Further, the isomer compounds were screened for their antibacterial and antifungal activities.     

Synthesis and pharmacological activity of the metabolites of Pratosartan

Three hydroxylated metabolites of 2-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (Pratosartan), which is a selective angiotensin II receptor antagonist, were synthesized in confirmation of their structures and in studies of their pharmacological properties. An MTPA ester of the human main metabolite was identified with the synthesized compound by comparing (1)H-NMR spectra, MS spectra, and HPLC retention time. The structure of the human main metabolite was confirmed to be (S)-(-)-2-(1-hydroxypropyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one ((S)-(-)-1). Also, the rat main metabolites were confirmed to be 8-hydroxylated compound (2) and 5-hydroxylated compound (3). These metabolites showed lower antagonistic activity than that of the parent compound.     

Synthesis and pharmacological evaluation of procaterol derivatives having a tert-amino group

A series of procaterol derivatives having a tert-amino group was synthesized. Among them, a morpholino derivative (4a, R1 = H, NR2R3 = morpholino) showed beta-selective and rather potent adrenoceptor stimulant activities in an in vivo assay using anesthetized dogs. On the other hand, a morpholinopropanol analogue (4j, R1 = CH3, NR2R3 = morpholino) showed 400 times less potent bronchodilator activity than that of 4a. Some of the compounds showed weak bronchodilator activities and weak effects on the heart. It seems that steric hindrance around the nitrogen atom of catecholamines has a significant influence on beta-adrenoceptor stimulant activities. Compound 4a also showed anti-allergic action estimated in terms of the inhibition of homologous passive cutaneous anaphylaxis in rats.     

Synthesis and pharmacological activity of 4-(4'-(chlorophenyl)-4-hydroxypiperidine) derivatives

A new series of 4-(4'-chlorophenyl)-4-hydroxypiperidine derivatives (2-5), substituted at nitrogen, were synthesized and tested as potential analgesic compounds as well as evaluated for their effect on hypotensive activity. Results showed that all the derivatives exhibit significant analgesic activity in male Wistar rats at a dose of 50 mg/kg of body weight after intramuscular injection, when tested by thermal stimuli (tail flick test). Pethidine was used as reference drug. Compounds 2, 3 and 5 produced reduction in blood pressure in normotensive rat.     

Synthesis and biological activity of apratoxin derivatives

This review covers the total asymmetric synthesis and biological evaluation of derivatives of the marine natural products known as the apratoxins.     

三氮唑类化合物的合成及抗真菌活性研究

近年来深部真菌感染的发病率和病死率逐年增加;同时由于真菌与人类细胞同为真核细胞,长期使用抗真菌药后对宿主具有相当的毒性.三氮唑类药物是目前治疗深部真菌感染的重要药物之一[1],代表药物有酮康唑、氟康唑、伊曲康唑等.该类药物抗菌谱广、毒性低、抗真菌作用强,但仍存在肝毒性较大、易产生耐药性等不良反应.