Calcium channel blockers are widely used in therapy for hypertension and angina pectoris, and among these blockers some 1,4-dihydropyridines (e.g. amlodipine, nitrendipine and nifedipine) have had widespread clinical use. In this work we investigated the vascular effects of four bis-1,4-dihydropyridines (bis-DHPs: 01-04), structurally related to nifedipine, in which a second 1,4-dihydropyridinic moiety was incorporated in the corresponding arylic moiety in para and meta position. Of these four bis-DHPs, the meta regioisomers (bis-DHP-03 and bis-DHP-04; 0.01-3.16 mg kg(-1)) and nifedipine induced a greater decrease on diastolic and systolic blood pressure than the para isomers (bis-DHP-01 and bis-DHP-02), as shown in two experimental models: normotensive and spontaneously hypertensive rats. Complementarily, bis-DHPs action was examined in intact and endothelium-denuded rat aorta, depolarized by KCl [80 mM] in one group and stimulated by noradrenaline (1 x 10(-7) M) in another and the corresponding IC(50) values were obtained (1.5 x 10(-6)-2. 4 x 10(-7)M). Later, the relaxing action of bis-DHP-03,04 and nifedipine on the contraction evoked by Ca(2+) in K(+)-depolarized rat aorta was analyzed and the corresponding EC(50) values for the meta isomers and nifedipine were obtained. The results showed a concentration dependent vasodilating activity in both KCl precontracted and noradrenaline stimulated aorta rings. The apparent order of potency with and without endothelium in both experimental models was nifedipine >bis-DHP-04 >bis-DHP-03. The cumulative concentration-effect curves for Ca(2+) in the presence of the bis-DHPs tested show the same potency order. Unlike nifedipine, the tested compounds are not photosensitive, which makes them more attractive in therapy for hypertension related diseases.

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In this work two series of isoindolines 1(a-g) and 2(a-g) were evaluated as possible inhibitors of lipoxygenase (LOX) by docking studies, as well as for the antiinflammatories isoindolilamides 3-5 and ibuprofen 6, as part of a theoretical study to found dual LOX/ COX inhibitory activities. Therefore, dihydrodimethylbenzofurane 7, licofelone 8 and darbufelone 9 were also evaluated, which are wellknown as dual LOX/COX inhibitors and consequently, in this work they were used to identify their binding sites on the LOX and compared with those obtained from 1(a-g), 2(a-g) and 3 to 6 under study. Analysis of the results showed that all compounds under study could inhibit to the LOX, since they are binding in the same or close to the region as the compounds 7-9 taken as references. Several interactions of heteroatom of all compounds with the amino acid residues of binding sites of LOX were determined. The DG values were obtained for all the complexes (LOX-compound), among all the complexes, LOX-8 (-12.76 kcal/mol) resulted to be the most stable; and from the compounds under study, LOX-1f (-8.97 kcal/mol) resulted to be more stable than the other compounds tested. Whereas, theoretical dissociation constant values Kd (mM) were obtained. Among all compounds, 8 (0.000433 mM) showed more affinity to LOX; while from compounds under study, 1f (0.266 mM) exhibited more affinity to LOX. These results also show that compounds 1(a-g) and 2(a-g), and 3-6 could have a dual LOX/COX/ inhibition, as have been shown for 7-9 and from their similar docking study within the COX-1 and COX-2 previously reported.

Cytochrome P‐450 (P450)enzymes play an important role during the drug metabolism due to it catalyzes a great amoung of reactions. However, their use for in vitro assays has several limitations, the main one is the use of the cofactor (NADPH). In this work the catalytic activity of P450 using NADP+ reduced with silica hydride was evaluated. The results obtained showed that the reduction of NADP+ with silica hydride was concentration and time‐dependent. In addition, P450 mantained its activity when NADP+ and silica hydride were added during the reaction, however its activity was less than when NADPH was employed. It is due to the fact that silica hydride is able to reduce not only to NADP+ but also to iron atom from P450, avoiding or diminishing the aniline affinity by the active site. The reduction of the iron atom with silica hydride was corroborated by electronic paramagnetic resonance (EPR). On the other hand, when NADP+ was reduced with silica hydride before being added to the reaction, the P450 activity was better than when NADPH was used. Therefore, it is worthnoting that the use of NADP+ reduced with silica hydride before to be added to the reaction could be a good system for studying biotransformation reactions.