Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: The effect of different substitution patterns

New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)- glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease

NCS-Mediated Ipso-Halogenation of Arylboronic Acids in Water Using Sodium Halides

A mild, efficient, eco-friendly method for the regioselective halogenation of arylboronic acids in water has been reported. A transition-metal-free ipso-chlorination of arylboronic acids was performed in water, yielding aryl chlorides. Ipso-brominated and iodinated compounds were obtained under the same conditions using the corresponding halide salts. This eco-friendly method operates efficiently, even on activated or nonactivated systems, with good yields and selectivity

A novel synthesis of fused isothiazole ring systems

The reaction of aromatic and heteroaromatic aldehydes with bis(trimethylsilyl)sulfide leads to the corresponding thioaldehydes, which, through a fine tuning of the reaction conditions, are trapped both intermolecularly and intramolecularly, thus disclosing a novel methodology for the synthesis of fused isothiazole ring system

Recent Advances in Synthetic Strategies to 2,3-Dihydrobenzofurans

This review gives an overview on recent developments in methods for the construction of compounds with the 2,3-dihydrobenzo furan core in the period 2012 to 2019. Interest in 2,3-dihydrobenzofurans is constantly increasing. The methods are divided into intermolecular and intramolecular approaches. Intermolecular approaches are subdivided according to the parent intermediate for the key reaction, while intermolecular approaches are subdivided according by which bond is formed in the key reaction. The transformation of benzofurans to dihydrobenzofurans and other miscellaneous methods are also discussed. Approaches useful for the synthesis of natural products are emphasized. 1 Introduction 2 Intermolecular Approaches 2.1 o -Quinone Methides and o -Quinones 2.2 p -Quinone Methides and p -Quinones 2.3 Nitrogen-Containing Phenols and Quinones 2.4 o -Hydroxyphenylcarbonyl Derivatives and Phenols 2.5 Miscellaneous 3 Intramolecular Approaches 3.1 O-C2 Bond Forming 3.2 C2-C3 Bond Forming 3.3 C3-Aryl Bond Forming 3.4 O-Aryl Bond Forming 4 From BF to DHB 5 Rearrangements and Aromatizations

Biginelli Reaction and \u3b2-Secretase Inhibition: A Multicomponent Reaction as a Friendly Educational Approach to Bioactive Compounds

Multicomponent reactions (MCRs) represent very interesting tools to reach eco-friendly and sustainable transformations in organic chemistry. In particular, the Biginelli reaction furnishes a very easy approach to the synthesis of a library of biological active compounds in an academic course. Here we describe the realization of several experiments involving the synthesis of potential inhibitors of \u3b2-secretase by the Biginelli reaction. All of the obtained compounds were tested with a FRET fluorimetric assay. The experiments were proposed to students either at entry level or during advanced laboratory courses of organic and bioorganic chemistry. The learning objectives at the advanced level were to introduce the students to the practice of combinatorial synthesis and to the evaluation of biological activity of combinatorial libraries by enzyme inhibition assays. The meeting of the learning objectives was probed first by analyzing their daily performance in the laboratory and their increasing proactive attitude, and the contents of their final presentations. The resulting marks obtained by the students were compared with the average evaluation of their career. Second, the students were asked to evaluate the course and their own experience, and the outcome of their evaluation was compared with that of the teachers

The pseudo-symmetric n-benzyl hydroxyethylamine core in a new series of heteroarylcarboxyamide hiv-1 pr inhibitors: Synthesis, molecular modeling and biological evaluation

Here, we report the synthesis, enzyme inhibition and structure–activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P’ and P” and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/mL BSA. Compounds 9a–c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compare

[7,0]-metacyclophanes from biaryl coupling/macrocyclisation

The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century organic chemists have sought to develop new and more efficient aryl-aryl bond-forming methods (1). Cyclophanic natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophanic molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions (2). Among cyclophanic natural products, the diarylheptanoids are a structurally sub-class with their scaffold consisting of two benzene rings tethered by an oxygenated aliphatic heptyl chain. In this work we reported different metal catalysed approaches to obtain the biaryl motif of myricanol, a natural [7,0]-metacyclophane with very important and recently discovered biological activities (3),(4),(5),(6). (Figure 1) Figure 1 The desired product 1could be obtained from the functionalized linear diarylheptanoid 2 by Suzuki domino process (macrocyclisation by linkage of aryl moieties) or could be synthesized from ring closing metathesis of product 3 which derived from a biaryl coupling of fragments 4 and 5. (1) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107 (1), 174–238. (2) Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29 (8), 899-934. (3) Jones, J. R.; Lebar, M. D.; Jinwal, U. K.; Abisambra, J. F.; Koren, J.; Blair, L.; O’Leary, J. C.; Davey, Z.; Trotter, J.; Johnson, A. G.; Weeber, E.; Eckman, C. B.; Baker, B. J.; Dickey, C. A. J. Nat. Prod. 2011, 74 (1), 38–44. (4) Martin, M. D.; Calcul, L.; Smith, C.; Jinwal, U. K.; Fontaine, S. N.; Darling, A.; Seeley, K.; Wojtas, L.; Narayan, M.; Gestwicki, J. E.; Smith, G. R.; Reitz, A. B.; Baker, B. J.; Dickey, C. A. ACS Chem. Biol. 2015, 10 (4), 1099–1109. (5) Dai, G. H.; Meng, G. M.; Tong, Y. L.; Chen, X.; Ren, Z. M.; Wang, K.; Yang, F. Phytomedicine 2014, 21 (11), 1490–1496. (6) Dai, G.; Tong, Y.; Chen, X.; Ren, Z.; Ying, X.; Yang, F.; Chai, K. Int. J. Mol. Sci. 2015, 16 (2), 2717–2731

New heteroaryl carbamates: synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors

New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors

Two novel precursors of the hiv-1 protease inhibitor darunavir target the UPR/proteasome system in human hepatocellular carcinoma cell line HepG2

Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anti-cancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates

A novel aminohydroxy sulfonamide formulated in PEGylated liposomes with potential antitumor activity

Cancer ranks as a leading cause of death worldwide, with liver cancer being one of the most commonly diagnosed. Currently, several molecules are being studied in order to find new therapeutic options that can reduce cancer recurrence rate and increase patient survival. This study proposes PEGylated liposomes for the delivery of a newly synthesized aminohydroxy sulfonamide, BupM-NH2, which has shown dose-dependent cytotoxicity towards hepatic tumor cells. The prepared PEG-liposomes were nanosized, spherical, and unilamellar, as shown by light scattering data and cryo-TEM micrographs. The physical stability of the PEG-liposomes was preserved when tested in simulated body fluids. Similar results were found for the storage stability evaluation. Furthermore, the PEG-liposomes efficiently entrapped BupM-NH2 and modulated its release. The antitumor activity of BupM-NH2 in PEG-liposomes was assessed in vitro in hepatocarcinoma cells. The viability assay showed that PEG-liposomes were able to control the release of BupM-NH2 over time and induce the death of HepG2 cells at a concentration about two-times lower than that required by free BupM-NH2 (IC50: 33.31 vs. 57.05 μM). Furthermore, the liposomal formulation showed a less cytotoxic effect against non-cancerous cell line (IHH) compared to the free molecule (IC50 > 200 vs. 106.9 μM), encouraging further investigation to confirm its effective and safe use