Medicinal Chemistry - Volume 10, Issue 2, 2014

Aerosolized therapies have been used in everyday clinical practice for decades. Experimentation with different delivery systems have led to the creation of aerosolized insulin, antibiotics, gene therapy and chemotherapy. Several of these therapies are already clinically available while others are being investigated in active clinical trials. The main factors affecting the efficiency and safety of the aerosolized therapies are the production of the aerosol, distribution/deposition of the aerosol throughout the lung parenchyma, respiratory defense mechanisms and tissue/pharmaceutical molecule interactions. Current methods of aerosol production and distribution will be presented along with an overview of the respiratory defense mechanisms. In addition, methods of aerosol evaluation in conjunction with a future perspective of the potential development of aerosol therapies will be presented.

Background: Recently the benefit of subcutaneously applied dehydroepiandrosterone (DHEA) during sepsis was demonstrated. It was therefore supposed that the impact of DHEA might be induced by its metabolite androstenediol produced via conversion in subcutaneous tissue. Thus we postulate a comparable impact of intravenously applied androstenediol like DHEA. Material and Methods: Male NMRI mice were subjected to sham-operation (laparotomy) or sepsis (cecal ligation and puncture). Animals received saline, DHEA (20 mg/kg/day) subcutaneously, androstenediol (20 mg/kg/day) subcutaneously and androstenediol (10 mg/kg/day) intravenously. During 48h of sepsis and treatment clinical parameters such as survival and body temperature were observed. Termination of animals was performed 48 hrs after induction of sepsis in order to monitor splenocyte apoptosis (Annexin V binding capacity), cytokine release (IL-10 and TNF-α, ELISA), and immunological capacity by DTH-Reaction (Delayed type of hypersensitivity). Results: Subcutaneous and intravenous androstenediol administration improved the survival rate of septic mice 48 hrs after induction of CLP like subcutaneous administration of DHEA. (86% vs 53%). This effect was paralleled by a restoration of splenocyte proliferation and DTH reaction, a decreased cellular apoptosis rate of splenocytes, and an attenuation of cytokine release. Conclusions: Administration of androstenediol induces an increased survival rate and improved cellular immune functions in septic mice. This effect was detected independent of the way of administration and is comparable to those effects induced by subcutaneous DHEA administration. With respect to clinical use during critical illness, intravenous administration of androstenediol seems to be an alternative to subcutaneous DHEA administration.

This paper describes the synthesis of a series of new N-arylpiperazine derivatives of pyridine and 2-pyridone. The in vitro pharmacological study indicated that all of the compounds possess affinity towards α1-adrenoceptors, with exception of 6d, and are selective over α2 receptor. The most potent compound 5f displayed 62-fold α2/α1 selectivity with Ki value of 27.3 nM for α1 receptor. Selectivity of other ligands ranged from 6 to more than 146-fold. Hydrochlorides of selected compounds with the best α1-adrenoceptor affinity (7b, 7e, 7f, 8b) were tested in vivo (hypotensive activity test in rats) and the results proved their α-adrenoreceptor antagonistic activity. Furthermore, the lipophilicity of the investigated compounds has been assessed experimentally and in silico.

In our previous paper we have reported the synthesis and biological activity of a cyclic analog, Tyr-c(D-Lys- Phe-Phe-Asp)-NH2, based on endomorphin-2 (EM-2) structure. This analog displayed high affinity for the '-opioid receptor, was much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) injection. Even more importantly, the cyclic analog elicited weak analgesia also after peripheral administration, giving evidence that it was able to cross, at least to some extent, the blood-brain barrier (BBB). Here we describe further modifications of this analog aimed at enhancing brain delivery by increasing lipophilicity. Two new cyclic pentapeptides, Tyr-c(D-Lys-D-1-Nal-Phe-Asp)-NH2 and Tyr-c(D-Lys-D-2-Nal-Phe-Asp)-NH2 (where 1-Nal=1- naphthyl-3-alanine, 2-Nal=2-naphthyl-3-alanine) were synthesized and evaluated in biological assays. Both analogs showed high '-opioid receptor affinity and agonist activity and were stable in the rat brain homogenates. Unfortunately, the increase of lipophilicity was achieved at the expense of water solubility. The analog with D-2-Nal residue showed strong analgesic effect when given i.c.v. but could not be tested after intravenous (i.v.) administration where higher concentrations of the compound are required. However, this analog showed inhibitory effect on gastrointestinal (GI) motility in vivo, providing an interesting approach to the development of peripherally restricted agents that could be useful for studying gastrointestinal disorders in animal models.

β-secretase (BACE-1) plays a pivotal role in the β-Amyloid plaques formation, which is responsible for progressive cognitive and memory loss commonly found in Alzheimer disease patients. As a consequence, it has been considered as a good target for drug development efforts. Early work focused on the synthesis of peptidomimetics, but poor pharmacokinetics profile prevented advancing lead compounds to clinical trials. As an alternative, aminoimidazoles, aminohydantoins and aminopyridines derivatives that inhibit BACE-1 were designed. Herein we report statistically sound descriptor- based (r2 = 0.87, q2 = 0.85, 6 PCs) and fragment-based (r2 = 0.91, q2 = 0.84, 6 PCs) QSAR models, that show high predictive ability (r2 pred = 0.84, averaged r2m=0.78) and underscore polar interactions that are important for BACE-1 inhibition.

Two novel series of potent and selective matrix metalloproteinase (MMP) inhibitors, involving unique binding mode at the active site and not interacting with the catalytic zinc, were collectively investigated to quantify their inhibition actions in relation with chemometric descriptors. Significant correlations, between their MMP13 inhibition activity and 2D-descriptors, were obtained through the combinatorial protocol in multiple linear regression (CP-MLR) computational procedure. The derived bi-variant models, validated internally and externally, were able to account for 86.5% of variance in the observed MMP13 inhibition activities. The filtered descriptors, from CP-MLR, satisfactorily explained the biological phenomenon under investigation. However the descriptors, MPC10, N-075 and C-030 accounting, respectively, for molecular path (bond) count of order 10, the structural fragments CH--N--CH and N--CH--N of aromatic ring remained prime to address the MMP13 inhibition actions of the compounds. From the highest significant correlations, it appeared that the higher value of MPC10 and absence of these aromatic ring fragments, are conducive in further improvement of MMP13 inhibition activity of a compound. The partial least squares (PLS) analysis has further confirmed the dominance of the identified descriptors. In the analysis, two-components remained optimum for these descriptors which are able to explain 89.3% of variances. Applicability domain (AD) analysis revealed that the suggested models have acceptable predictability. All the compounds remained within the AD of the proposed models and were evaluated correctly. Based on the inferences drawn from the study, some new analogues were suggested for further exploration. Their predicted MMP13 inhibition activities were much higher than the highest active congener of the original series.

The syntheses of hydroxyethylsulfonamides, (2S,3R)-tert-butyl N-[4-(N-benzyl-4-R-phenylsulfonamido)-3- hydroxy-1-phenylbutan-2-yl]carbamates and (5) (2S,3R)-2-amino-4-[N-benzyl-4-R-benzenesulfonamido]-3-hydroxy-1- phenylbutane hydrochlorides (6), derived from (2S,3S)-Boc-phenylalanine epoxide, are reported. None of the compounds, containing the Boc group, showed activity against M. tuberculosis ATTC 27294, while compounds 6 did, with the most active compounds having R = p-Cl, p-Br and p-Me. Results indicate that the presence of a free amino group at C2 and the sulphonamide moiety are important for biological activity. The antimycobacterial activity of compounds 6 correlated well with the calculated lipophilicities, but not with the electronic effects of the substituents, R. All compounds 6 were highly cytotoxic against the hepatoma cell lineage Hep G2 A16. The X-ray crystal structure of compound [(6: R = Me).H2O] is also reported. In the propeller-like conformation adopted by the cation, the amino and hydroxy groups have a cis arrangement, and thus are suitably placed to form 5- membered chelates.

The mosquito Aedes aegypti (Diptera, Culicidae) is the vector of yellow and dengue fever. In this study, chemometric tools, such as, Principal Component Analysis (PCA), Consensus PCA (CPCA), and Partial Least Squares Regression (PLS), were applied to a set of fifty five active compounds against Ae. aegypti larvae, which includes terpenes, cyclic alcohols, phenolic compounds, and their synthetic derivatives. The calculations were performed using the VolSurf+ program. CPCA analysis suggests that the higher weight blocks of descriptors were SIZE/SHAPE, DRY, and H2O. The PCA was generated with 48 descriptors selected from the previous blocks. The scores plot showed good separation between more and less potent compounds. The first two PCs accounted for over 60% of the data variance. The best model obtained in PLS, after validation leave-one-out, exhibited q2 = 0.679 and r2 = 0.714. External prediction model was R2 = 0.623. The independent variables having a hydrophobic profile were strongly correlated to the biological data. The interaction maps generated with the GRID force field showed that the most active compounds exhibit more interaction with the DRY probe.

Eight novel dihydropyrimidine analogs named DHPM1-DHPM8 was synthesized in their hydrochloride salt form using one pot synthesis between methyl 2-chloro-4-(4-chlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate and substituted arylamines in isopropanol. The antimosquito effect of the test compounds were assessed against the adult mosquito Anopheles arabiensis. For adulticidal properties the test compounds were sprayed onto ceramic tiles and screened using the cone bio-assay method. The larvicidal activity was tested by monitoring larval mortality daily and up to 3 days of exposure. Repellency properties were tested in a feeding-probe assay using unfed female Anopheles arabiensis. Compounds DHPM1, DHPM4, DHPM5 and DHPM6 exerted larval mortality equivalent to temephos (trade name Abate, a commercial larvicidal compound). Compounds DHPM1 to DHPM5 repelled or knocked down 92 to 98% of mosquitoes exposed to rodent skin treated with the compounds. None of the compounds showed any significant activity against the adult mosquito Anopheles arabiensis.

A series of new N-pyrazolylbenzamides (5a–x) were synthesized by aroylation of 5-amino-1-phenyl-3-tbutylpyrazole. The structures of synthesized compounds were established based on spectral (FTIR, 1H NMR, ESI Mass) analysis and purity was ascertained by HPLC. The antibacterial screening revealed that seven molecules exhibited an excellent antibacterial activity and eight compounds demonstrated considerable antifungal activity. Three molecules of the series 5e, 5s and 5w were found to be highly effective against Klebsilla pneumoneia with MIC of 3.12 μg/ml. Compounds 5b, 5f, 5g and 5o exhibited significant antitubercular activity with MIC of 12.5 μg/ml.

The aim of this study was to synthesize and evaluate diazapentacyclic analogs for their acetylcholinesterase (AChE) inhibitory activity. The pentacyclic analogs were synthesized by one-pot three-component domino reactions in a microwave synthesizer. Most of the compounds exhibited moderate to good AChE inhibitory activity, compound 5i showed potent inhibitory activity with IC50 1.12±0.01 μM and this may provide a new lead for developing potential inhibitors for Alzheimer's disease.