Effect Produced by a Cyclooctyne Derivative on Both Infarct Area and Left Ventricular Pressure via Calcium Channel Activation.

BACKGROUND: There are reports which indicate that some cyclooctyne derivatives may exert changes in cardiovascular system; however, its molecular mechanism is not very clear. OBJECTIVE: The aim of this study was to evaluate the biological activity of four cyclooctyne derivatives (compounds 1: to 4: ) produced on infarct area and left ventricular pressure. METHODS: Biological activity produced by cyclooctyne derivatives on infarct area was determinate using an ischemia/reperfusion injury model. In addition, to characterize the molecular mechanism of this effect, the following strategies were carried out as follows; i) biological activity produced by cyclooctyne derivative (compound 4: ) on either perfusion pressure or left ventricular pressure was evaluated using an isolated rat heart; ii) theoretical interaction of cyclooctyne derivative with calcium channel (1t0j protein surface) using a docking model. RESULTS: The results showed that cyclooctyne derivative (compound 4: ) decrease infarct area of in a dose-dependent manner compared with compound 1: to 3: . Besides, this cyclooctyne derivative increase both perfusion pressure and left ventricular pressure which was inhibited by nifedipine. Other theoretical data suggests that cyclooctyne derivative could interact with some aminoacid residues (Met83, Ile85, Ser86, Leu108, Glu114) involved in 1t0j protein surface. CONCLUSIONS: All these data indicate that cyclooctyne derivative increase left ventricular pressure via calcium channel activation and this phenomenon could be translated as a decrease of infarct area.

Biological Activity of a 4-Hydroxy-Furanyl-Benzamide Derivative on Heart Failure.

BACKGROUND: There are studies that suggest that some benzamide derivatives may exert effects on heart failure; however, their molecular mechanism is not very clear. OBJECTIVE: The aim of this research was to evaluate the biological activity of a 4-hydroxy-furanyl-benzamide derivative against heart failure translated as area infarct. METHODS: Biological activity produced by 4-hydroxy-furanyl-benzamide derivative against heart failure was determinate using an ischemia-reperfusion injury model. In addition, the effects exerted by the 4-hydroxy-furanyl-benzamide derivative on left ventricular pressure (LVP) was evaluated in the absence or presence of some drugs such as yohimbine, butaxamine, methoctramine and L-NAME using a model of rat heart isolated. RESULTS: The results showed that 4-hydroxy-furanyl-benzamide derivative decrease both infarct area and LVP. However, the effect produced by 4-hydroxy-furanyl-benzamide derivative on LVP was inhibited in the presence of both methoctramine and L-NAME. CONCLUSIONS: All these data suggest that biological activity produced by 4-hydroxy-furanyl-benzamide derivative on left ventricular pressure is through of both M2-muscarinic receptor and nitric oxide synthase enzyme activation. It is important to mention that this phenomenon results as a decrease of both infarct area and heart failure.

Evaluation of Biological Activity of a Diazocine Derivative against Heart Failure Using an Ischemia-Reperfusion Injury Model.

BACKGROUND: There are studies, which suggest that some diazocine derivatives can exert effects on the cardiovascular system; however, these effects are not very clear. OBJECTIVE: The aim of this research was to evaluate the biological activity of a diazocine derivative against heart failure translated as area infarct. METHODS: Biological activity produced by diazocine derivatives against heart failure was determinate using an ischemia/reperfusion injury model. Besides, to characterize the molecular mechanism of effect exerted by diazocine derivative on left ventricular pressure (LVP) was determinate in an isolated rat heart model using nifedipine, PINAME TXA2, and quinalizarin as controls. RESULTS: The results showed that diazocine derivative decrease the infarct area and increase the LVP. However, the effect produced by diazocine derivative on LVP was inhibited in the presence of quinalizarin. CONCLUSIONS: The results indicate that biological activity produced by diazocine derivative on left ventricular pressure is through protein CK2 activation; this phenomenon could be translated as a decrease in both infarct area and heart failure.

Synthesis and Biological Activity of the Pyridine-hexacyclic-steroid Derivative on a Heart Failure Model.

BACKGROUND: Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. OBJECTIVE: The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. METHODS: The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. RESULTS: The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. CONCLUSION: It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.

Design and Synthesis of an Aniline Derivative with Biological Activity on Heart Failure.

BACKGROUND: Several compounds have been synthesized as a therapeutic alternative for heart failure; however, its preparation requires special conditions. OBJECTIVE: The aim of this study, was to synthesize some aniline derivatives (4-9) from 3- ethynylaniline to evaluate their biological activity against heart failure. METHODS: The synthesis of aniline derivatives involved a series of reactions such as etherification, addition, and cyclization. The structure of all compounds obtained was confirmed by spectroscopic and spectrometric methods. In addition, to evaluate the biological activity of compounds, an ischemia/reperfusion injury model was used. RESULTS: The results showed that compound 8 decreases heart failure, which translates into a decrease in the infarction area compared to compounds 4-7 and 9. CONCLUSION: This study reports a facile method for the preparation of aniline derivatives. This method offers some advantages such as; a simple procedure, low cost, and easy work up. In addition, compound 8 showed an interesting biological activity against heart failure. This phenomenon is particularly interesting because the biological activity induced by this compound could involve a molecular mechanism that is different from other drugs used for the treatment of heart failure.

Effective synthesis of a hexacyclic-steroid derivative from 4-hydroxyestrone.

Several studies have been reported for the preparation of hexacyclic-steroid derivatives; however, some reagents are expensive and require special conditions for handling. In this way, the objective of this study was to synthesize a hexacyclic-steroid derivative from 4-hydroxyestrone. The chemical structure was evaluated through both 1H NMR and 13C NMR spectroscopic analysis. The results showed good performance of the hexacyclic-steroid derivative. In conclusion in this study, an easy method for the preparation of the hexacyclic-steroid derivative is reported.

Design and synthesis of a new furan-steroid-propanone derivative using some chemical strategies.

There are several reports for the preparation of furan derivatives using some protocols which requires special conditions. In this way, the aim of this study was to synthesize a new furan-steroid-propanone derivative from both 17α-ethynylestradiol and 2-nitro-17α-ethynylestradiol using some series of reactions such as aldolization, 2 + 2 addition and etherification. The chemical structure was evaluated through both 1H NMR and 13C NMR spectroscopic analysis. The results showed a good yielding from furan-steroid derivative. In conclusion, this investigation provides a facile synthesis of a new furan-steroid-propanone derivative, using some reagents which are not expensive and do not require special conditions for handling.

Design and synthesis of two new steroid derivatives with biological activity on heart failure via the M2-muscarinic receptor activation.

Several drugs have been prepared to treat of heart failure using some protocols which require dangerous reagents and specific conditions. The aim of this study was to synthesize a series of steroid derivatives (compounds 2 to 18) using some chemical strategies. The biological activity of steroid derivatives against heart failure was evaluated using an ischemia/reperfusion model. In addition, the effect exerted by compounds 4 or 5 on left ventricular pressure was evaluated in the absence or presence of yohimbine, butaxamine and methoctramine. The results showed that 1) both compounds 4 or 5 significantly decrease the heart failure (translated as infarct area) compared with the compounds 2, 3 and 6-18. In addition, the compound 4 and 5 decreased the left ventricular pressure in a dose-dependent manner and this effect was significantly inhibited in the presence of methoctramine (p = 005). In conclusion, the compounds 4 or 5 decrease both the infarct area and left ventricular pressure via M2-muscarinic receptor activation.

Synthesis and Biological Activity of a Bis-steroid-Methanocyclobutanaphthalene- dione Derivative against Ischemia/Reperfusion Injury via Calcium Channel Activation.

BACKGROUND: There is some experimental data on the effect exerted by some steroid derivatives against ischemia/reperfusion injury; however, the molecular mechanism is very confusing, perhaps this phenomenon could be due to the protocols used and/or differences in the chemical structure of each one of the steroid derivatives. OBJECTIVES: The aim of this study was to synthesize a new bis-steroid-methanocyclobutanaphthalene- dione derivative using some tools chemical. METHODOLOGY: The biological activity exerted by the bis-steroid-methanocyclobutanaphthalene- dione derivative against ischemia/reperfusion injury was evaluated in an isolated heart model using noradrenaline, milrinone, dobutamine, levosimendan, and Bay-K- 8644 as controls. In addition, other alternative experiments were carried out to evaluate the biological activity induced by the bis-steroid-methanocyclobuta-naphthalene-dione derivative against left ventricular pressure in the absence or presence of nifedipine. RESULTS: The results showed that 1) the bis-steroid-methanocyclobuta-naphthalene-dione derivative significantly decreases the ischemia-reperfusion injury translated as a decrease in the the infarct area in a similar manner to levosimendan drug; 2) both bis-steroidmethanocyclobuta- naphthalene-dione and Bay-K-8644 increase the left ventricular pressure and 3) the biological activity exerted by bis-steroid-methanocyclobuta-naphthalenedione derivative against left ventricular pressure is inhibited by nifedipine. CONCLUSION: In conclusion, the bis-steroid-methanocyclobuta-naphthalene-dione derivative decreases the area of infarction and increases left ventricle pressure via calcium channels activation; this phenomenon could constitute a new therapy for ischemia/reperfusion injury.

Design and synthesis of an indol derivative as antibacterial agent against Staphylococcus aureus.

Several indole derivatives with antibacterial activity have been prepared using different protocols; however, some require special reagents and conditions. The aim of this study involved the synthesis of some indole derivatives using estrone and OTBS-estrone as chemical tools. The synthesis of the indole derivatives involves reactions such as follows: (1) synthesis of two indol derivatives (4 or 5) by reaction of estrone or OTBS-estrone with phenylhydrazine in medium acid; (2) reaction of 4 or 5 with 6-cloro-1-hexyne in medium basic to form two hexynyl-indol (7 or 8); (3) preparation of indol-propargylic alcohol derivatives (10 or 11) by reaction of benzaldehyde with 7 or 8 in medium basic; (4) synthesis of indol-aldehydes (12 or 13) via oxidation of 10 or 11 with DMSO; (5) synthesis of indeno-indol-carbaldehyde (15 or 16) via alkynylation/cyclization of 12 or 13 with hexyne in presence of copper(II); (6) preparation indeno-indol-carbaldehyde complex (19 or 20) via alkynylation/cyclization of 12 or 13 with 1-(hex-5-yn-1-yl)-2-phenyl-1H-imidazole. The antibacterial effect exerted by the indol-steroid derivatives against Streptococcus pneumoniae and Staphylococcus aureus bacteria was evaluated using dilution method and the minimum inhibitory concentration (MIC). The results showed that only the compound 19 inhibit the growth bacterial of S. aureus. In conclusion, these data indicate that antibacterial activity of 19 can be due mainly to functional groups involved in the chemical structure in comparison with the compounds studied.

Design and synthesis of four steroid-oxirane derivatives using some chemical tools.

This study involved the synthesis of several new derivatives of progesterone, 11a-hydroxyprogesterone, 11a-t-butyldimethylsilanyloxyprogesterone, and andrenosterone. The new derivatives were prepared by condensation of the 4-en-3-one moiety of the four steroids with 2-hydroxy-1-naphthaldehyde to afford a series of 4-(R)-hydroxy-(2-hydroxynaphtalen-1-yl) adducts. These adducts were further modified by cyclization reactions of the dihydroxynaphthalenyl moieties with succinic acid, and the resulting cyclic succinates were then condensed with ethylenediamine to form imine derivatives at all available carbonyl groups. These compounds were then derivatized by N-acylation of the 11- and 17-imine nitrogens with chloroacetyl chloride and the resulting chloroacetamides were then condensed with 2-hydroxy-1-napthaldehyde in Darzens-type reactions forming the corresponding epoxy acetamides in the side chains. In addition, the chemical structure of steroid derivatives was confirmed by NMR spectroscopic data.

Evaluation of activity of an estrogen-derivative as cardioprotector drug using an ischemia-reperfusion injury model.

Myocardial ischemia/reperfusion injury is a serious problem involved in cardiovascular diseases. There data which indicate that some steroids induce cardioprotective effects on myocardial ischemia-reperfusion injury; however their activity and the molecular mechanism involved on myocardial ischemia-reperfusion injury are very confusing. Therefore, in this study some estrogen derivatives (compound 3 to 7) were synthesized with the objective of evaluating its activity on myocardial ischemia/reperfusion injury using an isolated heart model. Additionally, molecular mechanism involved in the activity exerted by the compounds 3 to 7 on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in absence or presence of following compounds; prazosin, metoprolol, indomethacin and nifedipine. The results showed that 7 reduce infarct size compared with the estrone and other estrogen derivatives (compounds 3, 4, 5, and 6). Other results showed that 7 significantly increase the perfusion pressure and coronary resistance in isolated heart in comparison with estrone, 3, 4, 5, and 6. Finally, other data indicate that 7 increased the left ventricular pressure in a dose-dependent manner; however, this phenomenon was significantly inhibited by nifedipine. In conclusion, all these data suggest that 7 exert a cardioprotective effect through calcium channels activation and consequently induce changes in the left ventricular pressure levels. This phenomenon results in decrease of myocardial necrosis after ischemia and reperfusion.

Design and synthesis of new dihydrotestosterone derivative with positive inotropic activity.

There are several reports which indicate that some steroid derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action of steroid derivatives at cardiovascular level is very confusing. In order, to clarify these phenomena in this study, two dihydrotestosterone derivatives (compounds 5 and 10) were synthesized with the objective of to evaluate its biological activity on left ventricular pressure and characterize their molecular mechanism. In the first stage, the Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the steroid derivatives. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the compound 5 was evaluated by measuring left ventricular pressure in absence or presence of following compounds; nifedipine, flutamide, indomethacin, prazosin, isoproterenol, propranolol and metoprolol. The results showed that the compound 5 significantly increased the perfusion pressure and coronary resistance in comparison with dihydrotestosterone, compound 10 and the control conditions. Other data indicate that 5 increase left ventricular pressure in a dose-dependent manner (0.001-100 nM); nevertheless, this phenomenon was significantly inhibited only by propranolol or metoprolol at a dose of 1 nM. These data suggest that positive inotropic activity induced by the compound 5 is through ß1-adrenergic receptor however, this effect was independent of cAMP levels. This phenomenon is a particularly interesting because the positive inotropic activity induced by this steroid derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.

Synthesis and antibacterial activity evaluation of two androgen derivatives.

In this study two androgen derivatives were synthesized using several strategies; the first stage an aza-steroid derivative (3) was developed by the reaction of a testosterone derivative (1) with thiourea (2) in presence of hydrogen chloride. The second step, involves the synthesis of an amino-steroid derivative (4) by the reaction of 1 with 2 using boric acid as catalyst. The third stage was achieved by the preparation of an aminoaza-androgen derivative (6) by the reaction of 3 with ethylenediamine using boric acid as catalyst. In addition, the compound 6 was made reacting with dihydrotestosterone to form a new androgen derivative (7) in presence of boric acid. The following step was achieved by the reaction of 7 with chloroacetyl chloride to synthesize an azetidinone-androgen derivative (8) using triethylamine as catalyst. Additionally, a thiourea-androgen derivative (9) was synthetized by the reaction of 4 with dihydrotestosterone using boric acid as catalyst. Finally, the compound 9 was made reacting with chloroacetyl chloride in presence of triethylamine to synthesize a new azetidinone-androgen derivative (10). On the other hand, antibacterial activity of compounds synthesized was evaluated on Gram negative (Escherichia coli and Vibrio cholerae) and Gram positive (Staphylococos aureus) bacteria. The results indicate that only the compound 3 and 8 decrease the growth bacterial of E. coli and V. cholerae. Nevertheless, growth bacterial of S. aureus was not inhibited by these compounds. These data indicate that antibacterial activity exerted by the compounds 3 and 8 depend of their structure chemical in comparison with the controls and other androgen derivatives that are involved in this study.

Evaluation of activity inotropic of a new steroid derivative using an isolated rat heart model.

There are studies which indicate that some steroid derivatives have inotropic activity; nevertheless, the cellular site and mechanism of action at cardiovascular level is very confusing. In order, to clarify these phenomena in this study, a new estradiol derivative was synthesized with the objective of to evaluate its biological activity on left ventricular pressure and characterize their molecular mechanism. The Langendorff technique was used to measure changes on perfusion pressure and coronary resistance in an isolated rat heart model in absence or presence of the estradiol derivative. Additionally, to characterize the molecular mechanism involved in the inotropic activity induced by the OTBDS-estradiol-hexanoic acid derivative was evaluated by measuring left ventricular pressure in absence or presence of following compounds; tamoxifen, prazosin, metoprolol, indomethacin and nifedipine. The results showed that the OTBDS-estradiol-hexanoic acid derivative significantly increased the perfusion pressure and coronary resistance in comparison with the control conditions. Additionally, other data indicate that OTBDS-estradiol-hexanoic acid derivative increase left ventricular pressure in a dose-dependent manner (0.001 to 100 nM); nevertheless, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These data suggest that positive inotropic activity induced by the OTBDS-estradiol-hexanoic acid derivative is via activation of L-type calcium channel. This phenomenon is a particularly interesting because the positive inotropic activity induced by this steroid derivative involves a molecular mechanism different in comparison with other positive inotropic drugs.

Activity exerted by a testosterone derivative on myocardial injury using an ischemia/reperfusion model.

Some reports indicate that several steroid derivatives have activity at cardiovascular level; nevertheless, there is scarce information about the activity exerted by the testosterone derivatives on cardiac injury caused by ischemia/reperfusion (I/R). Analyzing these data, in this study, a new testosterone derivative was synthetized with the objective of evaluating its effect on myocardial injury using an ischemia/reperfusion model. In addition, perfusion pressure and coronary resistance were evaluated in isolated rat hearts using the Langendorff technique. Additionally, molecular mechanism involved in the activity exerted by the testosterone derivative on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in the absence or presence of the following compounds: flutamide, prazosin, metoprolol, nifedipine, indomethacin, and PINANE TXA2. The results showed that the testosterone derivative significantly increases (P = 0.05) the perfusion pressure and coronary resistance in isolated heart. Other data indicate that the testosterone derivative increases left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited (P = 0.06) by indomethacin and PINANE-TXA2 (P = 0.05) at a dose of 1 nM. In conclusion, these data suggest that testosterone derivative induces changes in the left ventricular pressure levels through thromboxane receptor activation.

New steroid derivative with hypoglycemic activity.

Data indicates that some steroid derivatives may induce changes on glucose levels; nevertheless, data are very confusing. Therefore, more pharmacological data are needed to characterize the activity induced by the steroid derivatives on glucose levels. The aim of this study was to synthesize a new steroid derivative for evaluate its hypoglycemic activity. The effects of steroid derivative on glucose concentration were evaluated in a diabetic animal model using glibenclamide and metformin as controls. In addition, the pregnenolone-dihydrotestosterone conjugate was bound to Tc-99m using radioimmunoassay methods, to evaluate the pharmacokinetics of the steroid derivative over time. The results showed that the pregnenolone-dihydrotestosterone conjugate induces changes on the glucose levels in similar form than glibenclamide. Other data showed that the biodistribution of Tc-99m-steroid derivativein brain was higher in comparison with spleen, stomach, intestine liver and kidney. In conclusion, the pregnenolone-dihydrotestosterone conjugate exerts hypoglycemic activity and this phenomenon could depend of its physicochemical properties which could be related to the degree of lipophilicity of the steroidderivative.