Sinteza i farmakološko vrednovanje 2-supstituiranih-6-fenil-4,5-dihidropiridazin-3(2H)-ona kao snažnih srčanih stimulatora

The present study describes the synthesis and pharmacological evaluation of 2-substituted-6-(4-acylaminophenyl)-4,5-dihydropyridazin-3(2H)-ones as potent inodilating agents. The synthesis of target compounds 2-4 and 7-11 was acieved by Friedel-Crafts acylation of an appropriate anilide derivative with succinic anhydride or methylsuccinic anhydride and subsequent cyclization of intermediary keto acids with various hydrazine derivatives. The newly synthesized pyridazinone derivatives were evaluated for cardiotonic activity using isolated rat atria and for vasorelaxant activity using descending thoracic aortic rings of Wistar rats precontracted with phenylephrine (106 mol L1). 6-(4-Methanesulfonamidophenyl)-2-phenyl-4,5-dihydropyridazin-3(2H)-one (7) exhibited significant inodilatory properties and showed vasorelaxant activity in a nanomolar range (IC50 = 0.08 0.01 μmol L1).U radu je opisana sinteza i framakološko vrednovanje 2-supstituiranih-6-(4-acilaminofenil)-4,5-dihidropiridazin-3(2H)-ona kao snažnih srčanih stimulatora. Spojevi 2-4 i 7-11 sintetizirani su Friedel-Craftsovim acilaranjem odgovarajućeg anilida s anhidridom jantarne ili anhidridom metiljantarne kiseline te ciklizacijom intermedijarnih keto kiselina s različitim derivatima hidrazina. Kardiotonično djelovanje novosintetiziranih derivata piridazinona ispitano je na izoliranim atrijima štakora, a vazodilatirajuće djelovanje na silaznim torakalnim prstenima aorte prethodno kontrahiranim fenilefrinom (106 mol L1). 6-(4-Metansulfonamidofenil)-2-fenil-4,5-dihidropiridazin-3(2H)-on (7) pokazao je značajno stimulativno i vazodilatirajuće djelovanje u nanomolarnim koncentracijama (IC50 = 0,08 0,01 μmol L1)

Selective Phosphodiesterase 4 Inhibitors — Emerging Trends in Asthma Therapy (Antiasthmatics-3)

537-553Considerable interest has been generated in the potential utility of isozyme selective inhibitors of phosphodiesterases in the treatment of asthma and other inflammatory disorders. Heterogeneity in tissue distribution as well as their different functional roles make these enzymes very attractive targets for medicinal chemists. To date at least 11 different families of PDE isozymes are known, among which PDE 4 plays a major role in modulating the activity of virtually all cells involved in the inflammatory process. Inhibitors of this enzyme family display impressive antiasthmatic activity by reducing the bronchial smooth muscle tone and considerable anti-inflammatory activity. The review details the various classes of PDE 4 inhibitors structurally related to rolipram, nitraquazone and xanthines, which appear to be very attractive models for synthesis of novel selective PDE 4 inhibitors potentially useful for the treatment of asthma and chronic obstructive pulmonary diseases. Rationale for the use of PDE4 inhibitors in the treatment of asthma is also discussed

Synthesis and antineoplastic activity of some 16- benzylidene substituted steroidal oximes

2126-2137 Novel 16-benzylidine substituted steroidal oximes in the androstene series have been designed, synthesized and evaluated for in vitro antineoplastic activity at NCI, Bethesda, USA against 3-cell lines using one dose primary anticancer assay. Of the compounds tested, 3β-hydroxy derivatives 24 (DPJ-1059), 26 (DPJ-1081), 28 (DPJ-870), 30 (DPJ-818), 32 (DPJ-854) and 3β-acetoxy derivatives 25 (DPJ-1061), 27 (DPJ-1083), 31 (DPJ-817) and 33(DPJ-900) have been found to be quite active.</smarttagtype

Synthesis of 4-(benzamide)-and 4- (phthalimide)-substituted phenoxypropanolamines and their <img src='/image/spc_char/beta.gif' border=0>₁-, <img src='/image/spc_char/beta.gif' border=0>₂-adrenergic receptor binding studies

1441-1445N-[4-(2-Hydroxy-3-isopropylaminopropoxy)phenyl]-1-oxo-isoindoline 3 possess a cardioselective -adrenergic receptor binding affinity. Herein we attempted to synthesize the unreduced compound N-[4-(2-hydroxy-3-isopropyl­aminopropoxy)phenyl]phthalimide 4. But, reaction of N-[4-(2,3-epoxypropoxy)phenyl]phthalimide 10 with isopropyl­amine opened the phthalimide ring to give N-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-2-isopropylcarbamoylbenzamide 12 instead of 4 as expected. While treatment of 10 with tert-butylamine gives N-[4-(3-tert-butylamino-2-hydroxy­pro­poxy)phenyl]phthalimide 15. Further, reaction of 15 with isopropylamine opened the phthalimide ring to yield N-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-2-isopropylcarbamoylbenzamide 16. Also, reaction of N-[4-(2,3-epoxy­pro­poxy)­phenyl]-5,6-dimethoxyphthalimide 11 with isopropylamine affords the phthalimide ring opened analogue N-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-2-isopropylcarbamoyl-5,6-dimethoxybenzamide 13. Compounds 12, 13, 15 and 16 have been tested for their in vitro 1- and 2-adrenergic receptor binding affinity using turkey erythrocyte membrane (1) and lung homogenate of rats (2). The percentage inhibition of [3H]DHA binding to both 1- and 2-adrenergic receptors are compared with that of the standard non-selective -adrenergic blocking agent propranolol 1 and selective agent atenolol. All the tested compounds exhibit binding affinity to 1-adrenergic receptors at the tested concentration [10-5 M] and most of them (12, 15, 16) exhibit cardioselectivity (selectivity ratio > 1). The dimethoxy analogue 13 shows selectivity towards 2-adrenergic receptor (selectivity ratio < 1)

Synthesis and biological activity of 16-arylidene derivatives of estrone and estrone methyl ether

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Synthesis and biological activity of 16-arylidene derivatives of estrone and estrone methyl ether

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Synthesis and QSAR studies of 16-(3-methoxy-4-substituted benzylidene) androstene derivatives as anticancer agents

948-955 In a systematic effort aimed at identifying new steroidal cytotoxic agents with potent antipoliferative activity against cancer cells and developing their QSAR models, a series of 16-(3-methoxy-4-substituted benzylidene)androst-5-ene derivatives have been synthesized. The selected compounds are evaluated for antineoplastic activity against a panel of three human cell lines-breast, CNS and lungs at NCI, Bethesda, USA. The results presented herein indicate that compound 15-18, 21, 22, 25-30 are active anticancer agents. The QSAR investigation with multiple linear regression analysis has been applied to find a correlation between different calculated physicochemical parameters of these compounds and biological activity. Application of datasets by using CODESSA software has led to QSAR equations based on the 3 descriptors. The significant QSAR models have been obtained with R2 values which range from 0.9692-0.8225 and good predictive performance (q2 range: 0.9264-0.7121). These models are expected to be useful for the anticancer screening of androstene derivatives having substitution at position 3,16 and 17 of steroid nucleus. </smarttagtype

Synthesis and biological activity of 16β-morpholinosteroid derivatives

363-367Fusion of morpholine at the 16 position of the steroid nucleus has been carried out to prepare monoquaternary 6,7 and 8 and bisquaternary ammonium compounds 13 and 14. Compounds 13 and 14 partly resemble chandonium iodide in structure. All the compounds have been evaluated for their neuromuscular blocking and ganglion blocking activities. The compounds 3, 4 5, 11 and 12 have been screened for antineoplastic activity at NCI, Bethesda

Synthesis and biological activity of some D-ring modified estrone derivatives

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Synthesis of 4-(1-oxo-isoindoline)-, 4-(5, 6-dimethoxy-1-oxo-isoindoline) and 4-acetamido-substituted phenoxy-3-amino-propane derivatives and their β₁-,β₂-adrenergic receptor binding studies

2808-2813In continuation to our previous study of 4-(1-oxo-isoindoline)-and 4-(5,6-dimethoxy-1-oxo-isoindoline)-substituted phenoxypropanolamine as potential cardioselective β-adrenergic blocking agents, the synthesis of 4-(1-oxo-isoindoline) and 4-(5,6-dimethoxy-1-oxo-isoindo line)-substituted phenoxy-3-amino-propane derivatives and their beta adrenoceptor binding affinity and selectivity in turkey erythrocyte membrane (β1) and lung homogenate of rats (β2) is reported. Also 4-acetamido substituted derivatives are synthesized and tested. All the tested compounds exhibit better cardioselectivity, with the 4-acetamido substituted derivatives being the most cardioselective. N-{4-[3-(3,4 Dimethoxyphenylethylamino)propoxy]phenyl}-1-oxo-isoindoline 7 hydrochloride shows β1-adrenergic receptor binding affinity lower than propranolol, but comparable to that of atenolol with better cardioselectivity. Compound 7 has been selected for further pharmacological investigations