Alkene carboamination/oxidative denitrogenation of 3-allyl-3-hydrazinylindolin-2-ones: one-pot entry to spirocyclopropyloxindoles.

A one-pot protocol, consisting of a Pd-catalysed carboamination reaction, followed by N-deprotection and oxidative denitrogenation, has been developed for the synthesis of diversely substituted spirocyclopropyloxindoles, in yields up to 73% and with diastereoselectivity close to 1 : 1. Readily accessible starting materials, mild reaction conditions, an easy to operate one-pot procedure and good functional group tolerance make this transformation a versatile tool for the synthesis of substituted spirocyclopropyloxindoles. This protocol successfully works on the gram-scale and allows access to both diastereoisomers separately. A plausible mechanism was proposed, and a series of post-transformations were performed on the obtained products, showing their remarkable synthetic versatility.

Enantiopure ß-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions.

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure ß-substituted ß-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the ß-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.

Computational Design, Synthesis, and Biophysical Evaluation of ß-Amido Boronic Acids as SARS-CoV-2 Mpro Inhibitors.

The COVID-19 pandemic has given a strong impetus to the search for antivirals active on SARS-associated coronaviruses. Over these years, numerous vaccines have been developed and many of these are effective and clinically available. Similarly, small molecules and monoclonal antibodies have also been approved by the FDA and EMA for the treatment of SARS-CoV-2 infection in patients who could develop the severe form of COVID-19. Among the available therapeutic tools, the small molecule nirmatrelvir was approved in 2021. It is a drug capable of binding to the Mpro protease, an enzyme encoded by the viral genome and essential for viral intracellular replication. In this work, by virtual screening of a focused library of ß-amido boronic acids, we have designed and synthesized a focused library of compounds. All of them were biophysically tested by microscale thermophoresis, attaining encouraging results. Moreover, they also displayed Mpro protease inhibitory activity, as demonstrated by performing enzymatic assays. We are confident that this study will pave the way for the design of new drugs potentially useful for the treatment of SARS-CoV-2 viral infection.

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines.

Addressing the asymmetric synthesis of oxindole-based α-aminoboronic acids, instead of the expected products we disclosed the efficient homocoupling of oxindole-based N-tert-butanesulfinyl imines, with the generation of chiral, quaternary 1,2-diamines in a mild and completely stereoselective way. The obtained 3,3'-bisoxindole derivatives were fully characterized by NMR and single-crystal X-ray diffraction analysis and proved to be single diastereoisomers and atropisomers. A plausible mechanism for the one-pot Cu(II)-catalyzed Bpin addition to the isatin-derived ketimine substrate and subsequent homocoupling is described.

Highly diastereoselective entry to chiral oxindole-based ß-amino boronic acids and spiro derivatives.

We here describe the first Cu-catalysed, diastereoselective 1,2-addition of 1,1-diborylmethane to chiral ketimines for the synthesis of quaternary stereocenters and spiro compounds. The method provides easy access to a range of chiral, highly functionalized compounds, namely oxindole-based ß,ß'-disubstituted ß-amino boronates, boron-containing peptidomimetics and six-, seven-membered spirocyclic hemiboronic esters. Such unprecedented compounds are mostly obtained in high yields and easily isolated as single diastereoisomers, paving the way to a more intense exploitation of boron-containing compounds in diversity-oriented chemistry and drug-discovery programs. Concerning stereochemistry, the application of Ellman's auxiliary strategy allows in principle to access both steric series of target compounds.

Computational Design, Synthesis, and Biological Evaluation of Diimidazole Analogues Endowed with Dual PCSK9/HMG-CoAR-Inhibiting Activity.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which regulates circulating cholesterol levels. Consequently, the PCSK9 inhibition is a valuable therapeutic approach for the treatment of hypercholesterolemia and cardiovascular diseases. In our studies, we discovered Rim13, a polyimidazole derivative reducing the protein-protein interaction between PCSK9 and LDLR with an IC50 of 1.6 µM. The computational design led to the optimization of the shape of the PCSK9/ligand complementarity, enabling the discovery of potent diimidazole derivatives. In fact, carrying out biological assays to fully characterize the cholesterol-lowering activity of the new analogues and using both biochemical and cellular techniques, compound Dim16 displayed improved PCSK9 inhibitory activity (IC50 0.9 nM). Interestingly, similar to other lupin-derived peptides and their synthetic analogues, some compounds in this series showed dual hypocholesterolemic activity since some of them complementarily inhibited the 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Allylation of isatin-derived N-Boc-hydrazones followed by Pd-catalyzed carboamination reaction: an entry to 3-spiro-pyrazolidyl-oxindoles.

The indium-mediated allylation of novel 3-(2-Boc-hydrazono)indolin-2-one derivatives, followed by a palladium-catalysed carboamination reaction, is described to afford unprecedented spirocyclic oxindoles in good yields. The method provides an efficient access to both cis and trans diastereoisomers of highly functionalized compounds, bearing an N-Boc, 5-substituted pyrazolidine ring at the C3-oxindole spiro junction. The versatility of the method is fully demonstrated starting from a series of substituted isatins and employing a variety of aryl halides in the key cyclization step.

Improved sperm count and motility in young men surgically treated for cryptorchidism in the first year of life.

INTRODUCTION: The timing of surgery in cryptorchidism has been debated for a long time. Reports on histology suggest better fertility outcomes with early surgery, whereas evidence of long-term improved fertility still lacks sound data. The aim of this study is to analyze sperm count and motility in a cohort of young men operated on during the first 2 years of life for cryptorchidism. PATIENTS AND METHODS: A total of 78 young men (age, 18-26 years) surgically treated for cryptorchidism in the second year of life were recalled to evaluate testicular volume and sperm count and motility. Of the 78 young men, 51 accepted to participate to clinical and sperm evaluation. Relationship between total sperm count (TSC), sperm motility (SM), and age at surgery was investigated by Student t-test and Fisher test. Patients were divided into two groups: those patients who were submitted to surgery in their first year of life (Group A) and those patients who were submitted to surgery in their first and the second year of life (Group B). We investigated the ratio of those patients with normal sperm count to those patients with abnormal sperm count (we defined as normal TSC > 15 million and SM > 15%) and compared the mean TSC and SM in the two groups. RESULTS: TSC were slightly but not significantly higher in the first group (45.5 ± 15.5 million/mL vs. 36.5 ± 23.6 million/mL, p = 0.107) and SM (30.5% ± 11.3% vs. 26.5% ± 15.4%, p = 0.341). The percentage of patients with normal sperm count and motility were significantly higher in the first group: normal TSC was found in 26 of 27 patients (96.3%) in Group A versus 18 of 24 patients (75.0%) in Group B (p = 0.042), normal SM was found in 26 of 27 patients (96.3%) versus 16 of 24 patients (66.7%), respectively (p = 0.008). In the two groups, no statistically significant difference was found neither in the proportion of patients with bilateral cryptorchidism, in the position of the testes, nor in the ratio of subjects treated with hormonal therapy before being operated on. CONCLUSIONS: In formerly cryptorchid subjects submitted to surgery in the first 2 years of life, the percentage of patients with normal sperm count and motility is higher than 95%, with even better fertility prognosis if orchiopexy is performed in the first year of life.