Dizajniranje i sinteza novih derivata tiofenkarbohidrazida, tienopirazola i tienopirimidina s antioksidativnim i antitumorskim djelovanjem

2-Amino-5-acetyl-4-methyl-thiophene-3-carboxylic acid ethyl ester (1) and 5-acetyl-2-amino-4-methylthiophene-3-carbohydrazide (2) were synthesized and used as starting materials for the synthesis of new series of 1-(5-amino-4-(3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3a), 1-(5-amino-4-(4-chloro-3,5-dimethyl-1H-pyrazole-1-carbonyl)-3-methylthiophen-2-yl) ethanone (3b), 1-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) pyrazolidine-3,5-dione (4), (Z)-N\u27-(4-methyl-2-amino-5-acetylthiophene-3-carbonyl) formohydrazonic acid (5a), (Z)-ethyl-N\u27-(4-methyl-2-amino-5-acetylthiophene-3-carbonylformo hydrazonate (5b), 6-acetyl-3-amino-2,5-dimethylthieno2,3-dpyrimidin-4(3H)-one (8), 5-methyl-3-amino-2-mercapto-6-acetylthieno2,3-dpyrimidin-4(3H)-one (10) and 5-methyl-6-acetyl-2-thioxo-2,3-dihydrothieno2,3-dpyrimidin-4(1H)-one (12) as potential antioxidant and antitumor agents. Pharmacological results showed that compounds 6a, 6b, 8, 10 and 12 exhibited promising antitumor and antioxidant activity.Etilni ester 2-amino-5-acetil-4-metil-tiofen-3-karboksilne kiseline (1) i 5-acetil-2-amino-4-metiltiofen-3-karbohidrazid (2) sintetizirani su i upotrebljeni kao reaktanti u sintezi novih spojeva 1-(5-amino-4-(3,5-dimetil-1H-pirazol-1-karbonil)-3-metiltiofen-2-il) etanona (3a), 1-(5-amino-4-(4-klor-3,5-dimetil-1H-pirazol-1-karbonil)-3-metiltiofen-2-il) etanona (3b), 1-(4-metil-2-amino-5-acetiltiofen-3-karbonil) pirazolidin-3,5-diona (4), (Z)-N\u27-(4-metil-2-amino-5-acetiltiofen-3-karbonil) formohidrazonske kiseline (5a), (Z)-etil-N\u27-(4-metil-2-amino-5-acetiltiofen-3-karbonilformo hidrazonata (5b), 6-acetil-3-amino-2,5-dimetiltieno2,3-dpirimidin-4(3H)-one (8), 5-metil-3-amino-2-merkapto-6-acetiltieno2,3-dpirimidin-4(3H)-ona (10) i 5-metil-6-acetil-2-tiokso-2,3-dihidrotieno2,3-dpirimidin-4(1H)-ona (12) kao potencijalnih antioksidansa i citostatika. Farmakološka ispitivanja ukazuju na to da spojevi 6a, 6b, 8, 10 i 12 imaju značajno antitumorsko i antioksidativno djelovanje

Sinteza, antimikrobno i antitumorsko djelovanje nekoliko novih N-etil, N-benzil i N-benzoil-3-indolil heterocikličkih spojeva

A series of 1-(N-substituted-1H-indol-3-yl)-3-arylprop-2-ene-1-ones (2a,b-4a,b) were prepared and allowed to react with urea, thiourea or guanidine to give pyrimidine derivatives 5a,b–13a,b. Reaction of 2a,b-4a,b with ethyl acetoacetate in the presence of a base gave cyclohexanone derivatives 14a,b-16a,b. Reaction of the latter compounds with hydrazine hydrate afforded indazole derivatives 17a,b-19a,b. On the other hand, reaction of 2a,b-4a,b with some hydrazine derivatives, namely hydrazine hydrate, acetyl hydrazine, phenyl- hydrazine and benzylhydrazine hydrochloride, led to the formation of pyrazole derivatives 20a,b-31a,b. Moreover, reaction of 2a,b-4a,b with hydroxylamine hydrochloride gave isoxazole derivatives 32a,b-34a,b. The newly synthesized compounds were tested for their antimicrobial activity and showed that 4-(N-ethyl-1H-indol-3-yl)-6-(p-chlorophenyl)-pyrimidine-2-amine (11b) was the most active of all the test compounds towards Candida albicans compared to the reference drug cycloheximide. Eighteen new compounds, namely pyrimidin-2(1H)-ones 5a,b-7a,b, pyrimidin-2(1H)-thiones 8a,b-10a,b and pyrimidin-2-amines 11a,b-13a,b derivatives, were tested for their in vitro antiproliferative activity against HEPG2, MCF7 and HCT-116 cancer cell lines. 4-(N-ethyl-1H-indol-3-yl)-6-(p-methoxyphenyl)-pyrimidin-2-amine (11a) was found to be highly active with IC50 of 0.7 µmol L1.Sintetizirana je serija 1-(N-supstituiranih-1H-indol-3-il)-3-arilprop-2-en-1-ona (2a,b-4a,b) i podvrgnuta reakciji s ureom, tioureom ili gvanidinom, pri čemu su nastali derivati pirimidina 5a,b–13a,b. Reakcijom 2a,b-4a,b s etil-acetoacetatom u prisutnosti baze nastali su derivati cikloheksanona 14a,b-16a,b. Njihovom reakcijom s hidrazin hidratom dobiveni su derivati indazola 17a,b-19a,b. S druge strane, reakcijom 2a,b-4a,b s određenim derivatima hidrazina, tj. s hidrazin hidratom, acetil hidrazinom, fenilhidrazinom i benzilhidrazin hidrokloridom, nastali su derivati pirazola 20a,b-31a,b. Nadalje, reakcijom 2a,b-4a,b s hidroksilamin hidrokloridom dobiveni su derivati izoksazola 32a,b-34a,b. Pripravljeni spojevi ispitani su na antimikrobno djelovanje. Pokazalo se da je 4-(N-etil-1H-indol-3-il)-6-(p-klorfenil)-pirimidin-2-amin (11b) najaktivniji spoj za Candida albicans (ATCC 10231) uz cikloheksimid kao poredbeni lijek. Testirano je antitumorsko djelovanje in vitro osamnaest novih spojeva, tj. pirimidin-2(1H)-ona 5a,b-7a,b, pirimidin-2(1H)-tiona 8a,b-10a,b i pirimidin-2-amina 11a,b-13a,b na tumorske stanice HEPG2, MCF7 i HCT-116. Najaktivniji spoj bio je 4-(N-etil-1H-indol-3-il)-6-(p-metoksifenil)-pirimidin-2-amin (11a) uz IC50 0,7 µmol L1

Nonlinear modified positive position feedback control of cantilever beam system carrying an intermediate lumped mass

In this paper, we investigated the nonlinear oscillations, stability and resonance of a cantilever beam system which carrying an intermediate lumped mass. The response of amplitudes and phases of the differential equation governing is derived applying the multiple scale perturbation (MSP) method. The nonlinear vibration control is analyzed using a new nonlinear modified positive position feedback (MPPF) approach. The nonlinear approximate solutions for this system up to and inclusive the second order approximation are solved. The influence of various parameters on the system response is studied. The numerical solutions and amplitude response of this system are also studied and investigated. The stability and bifurcation of the cantilever beam system is determined applying the frequency response curves and phase plane technique. Comparison between numerical and analytical solutions is illustrated. Results demonstrated that controller structure has the most salient role in the suppression performance. Utilizing the nonlinear MPPF approach, the vibration amplitude is suppressed at the exact resonant frequency sufficiently and the subsequent peaks of the frequency range is reduced significantly compared to the positive position feedback (PPF) approach

Folic acid and melatonin ameliorate carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats

<p>Abstract</p> <p>This study investigated the protective effects of melatonin and folic acid against carbon tetrachloride (CCl4)-induced hepatic injury in rats. Oxidative stress, liver function, liver histopathology and serum lipid levels were evaluated. The levels of protein kinase B (Akt1), interferon gamma (IFN-γ), programmed cell death-receptor (Fas) and Tumor necrosis factor-alpha (TNF-α) mRNA expression were analyzed. CCl4 significantly elevated the levels of lipid peroxidation (MDA), cholesterol, LDL, triglycerides, bilirubin and urea. In addition, CCl4 was found to significantly suppress the activity of both catalase and glutathione (GSH) and decrease the levels of serum total protein and HDL-cholesterol. All of these parameters were restored to their normal levels by treatment with melatonin, folic acid or their combination. An improvement of the general hepatic architecture was observed in rats that were treated with the combination of melatonin and folic acid along with CCl4. Furthermore, the CCl4-induced upregulation of TNF-α and Fas mRNA expression was significantly restored by the three treatments. Melatonin, folic acid or their combination also restored the baseline levels of IFN-γ and Akt1 mRNA expression. The combination of melatonin and folic acid exhibited ability to reduce the markers of liver injury induced by CCl4 and restore the oxidative stability, the level of inflammatory cytokines, the lipid profile and the cell survival Akt1 signals.</p