M. Encarnación Camacho

Phenylpyrrole derivatives as neural and inducible nitric oxide synthase (nNOS and iNOS) inhibitors.

We have previously described a series of 3-phenyl-4,5-dihydro-1H-pyrazole derivatives as moderately potent nNOS inhibitors. As a follow up of these studies, several new 5-phenyl-1H-pyrrole-2-carboxamide derivatives have been synthesized, and their biological evaluation as in vitro inhibitors of both neural and inducible Nitric Oxide Synthase (nNOS and iNOS) is described. Some of these compounds show good iNOS/nNOS selectivity and the more potent compounds 5-(2-aminophenyl)-1H-pyrrole-2-carboxilic acid methylamide (QFF205) and cyclopentylamide (QFF212) have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in the MPTP model of Parkinsons disease.

Pyrazoles and pyrazolines as neural and inducible nitric oxide synthase (nNOS and iNOS) potential inhibitors (III).

We have previously described a series of 4,5-dihydro-1H-pyrazole as moderately potent nNOS inhibitors. As a follow up of these studies, we report here the preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1H-pyrazole and 1-alkyl-3-benzoyl-1H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS). None of the reported compounds exhibited significant iNOS or nNOS inhibition, although the 1-benzyl-3-(2-amino-5-chlorobenzoyl)-1H-pyrazole-5-carboxylic acid ethyl ester derivative (10l), which shows an inhibition of 50% versus iNOS at a 1mM final concentration and no activity against nNOS, is potentially amenable of further optimization. The reasons for the inactivity of the reported series are discussed on the basis of docking studies.

Development of Urea and Thiourea Kynurenamine Derivatives: Synthesis, Molecular Modeling, and Biological Evaluation as Nitric Oxide Synthase Inhibitors

Herein we describe the synthesis of a new family of kynurenamine derivatives with a urea or thiourea moiety, together with their in vitro biological evaluation as inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS, respectively), enzymes responsible for the biogenesis of NO. These compounds were synthesized from a 5‐substituted‐2‐nitrophenyl vinyl ketone scaffold in a five‐step procedure with moderate to high chemical yields. In general, the assayed compounds show greater inhibition of iNOS than of nNOS, with 1‐[3‐(2‐amino‐5‐chlorophenyl)‐3‐oxopropyl]‐3‐ethylurea (compound 5 n) being the most potent iNOS inhibitor in the series and the most iNOS/nNOS‐selective compound. In this regard, we performed molecular modeling studies to propose a binding mode for this family of compounds to both enzymes and, thereby, to elucidate the differential molecular features that could explain the observed selectivity between iNOS and nNOS.

Synthesis and biological evaluation of 4,5-dihydro-1H-pyrazole derivatives as potential nNOS/iNOS selective inhibitors. Part 2: Influence of diverse substituents in both the phenyl moiety and the acyl group.

In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS.

N,N′-Disubstituted thiourea and urea derivatives: design, synthesis, docking studies and biological evaluation against nitric oxide synthase

The synthesis and biological evaluation of new types of N,N′-disubstituted thiourea and urea derivatives as inhibitors of both neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) are described. These compounds have been designed by reduction of the carbonyl group in the thiourea and urea kynurenamine derivatives 3 previously synthesized by our research group. The synthetic route performed to this new family also allows us to obtain the molecules 3 with less synthetic steps and higher global yield. Regarding the biological results, in general, the new derivatives 4a–q inhibit the neuronal NOS isoform better than the inducible one. Furthermore, thioureas exhibit higher inhibition than ureas for both isoenzymes. Among all the tested compounds, 4g shows significant nNOS (80.6%) and iNOS (76.6%) inhibition values without inhibiting eNOS. This molecule could be an interesting starting point for the design of new inhibitors with application in neurological disorders where both isoenzymes are implicated such as Parkinsons disease.

The use of wiki to promote students’ learning in higher education (Degree in Pharmacy)

Nowadays, the expansion of new technologies in developed countries requires their inclusion in the higher educational systems, focused on the development of new skills to promote a continuous and independent learning process for the students. Internet technologies have reached a wide social diffusion, mainly among young people, and therefore the use of digital technologies at university, from smartphone apps to online collaboration tools, is becoming more and more embedded. This article describes the exploration of using wiki to promote the study of a degree in Pharmacy, particularly in the area of Pharmaceutical and Organic Chemistry, by creating a collaborative network that encourages group interaction instead of individual achievement. Our initiative is aimed at developing a number of skills and abilities of students and improving their academic performance and their comprehensive training. This work has been carried out with students, who followed Pharmaceutical Chemistries I and II, compulsory courses of the degree in Pharmacy, and it has been extended to other compulsory (Organic Chemistry II) and optional courses (Advanced Chemistry of Drugs), for a total of 200 students. Students have worked in teams on topics related to the subjects above indicated and have used wiki to develop their work. Opinion polls have shown a degree of satisfaction between high and very high in their performance, highlighting the benefits of using wiki in learning.

NMR and conformational studies of new 5‐phenylpyrrole‐carboxamide derivatives

The 1H and 13C NMR resonances of 22 5‐(5‐substituted‐2‐nitrophenyl)‐1H‐pyrrole‐2‐carboxamides, 22 5‐(5‐substituted‐2‐aminophenyl)‐1H‐pyrrole‐2‐carboxamides, and 9 5‐phenyl‐1H‐pyrrole‐2‐carboxamides were assigned completely using the concerted application of one‐ and two‐dimensional experiments (DEPT, gs‐HMQC and gs‐HMBC). NOE studies and conformational analysis confirm the preferred conformations of such compounds. Copyright

NMR assignments and structural characterization of new thiourea and urea kynurenamine derivatives nitric oxide synthase inhibitors

Keywords: 1H and 13C 1D NMR; 1H and 13C 2D NMR (HSQC; HMBC); NOESY; alkylthioureas; alkylureas

Synthesis of oxadiazoline and quinazolinone derivatives and their biological evaluation as nitric oxide synthase inhibitors

The synthesis of two new families of compounds with oxadiazoline and quinazolinone structures and their in vitro biological evaluation as inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS) are described. These derivatives have been obtained from cyclization of substituted benzohydrazides with acid anhydrides followed by reduction, using different synthetic procedures. Their structures were confirmed by high-resolution mass spectroscopy and 1H and 13C nuclear magnetic resonance data. In general, the assayed compounds show better inhibition values of nNOS than of iNOS, being 7d the most active derivative with a quinazolinone scaffold, and 6t the best oxadiazoline one and the best nNOS inhibitor of all tested compounds. The structure–activity relationships are discussed in terms of the effects of the substituents on both 2- and 3-positions of the heterocyclic rings.

1H and 13C NMR spectral assignment of N,N′‐disubstituted thiourea and urea derivatives active against nitric oxide synthase

The 1H and 13C NMR resonances of seventeen N‐alkyl and aryl‐N′‐[3‐hydroxy‐3‐(2‐nitro‐5‐substitutedphenyl)propyl]‐thioureas and ureas (1–17), and seventeen N‐alkyl or aryl‐N′‐[3‐(2‐amino‐5‐substitutedphenyl)‐3‐hydroxypropyl]‐thioureas and ureas (18–34), designed as NOS inhibitors, were assigned completely using the concerted application of one‐ and two‐dimensional experiments (DEPT, HSQC and HMBC). NOESY studies confirm the preferred conformation of these compounds. Copyright