Synthesis of Chiral Spirocyclopropanepenicillanates via [2 + 1] Annulation of 6-Alkylidenepenicillanates and Sulfur Ylides.

An unexplored reactivity of 6-()-alkylidenepenicillanates was unveiled, describing the synthesis of compounds having a cyclopropane ring spiro-fused to the penicillanic core. This was achieved via the in situ generation of sulfur ylide intermediates from the corresponding sulfur salts, which react with 6-()-alkylidenepenicillanates, leading to spirocyclopropanepenicillanates. The formal [2 + 1] cycloaddition, which involved the creation of three new chiral centers, proved to be diastereoselective, affording the new chiral spiropenicillanates in good yields.

High Instantaneous Inhibitory Potential of Bictegravir and the New Spiro-β-Lactam BSS-730A for HIV-2 Isolates from RAL-Naïve and RAL-Failing Patients.

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy.

Synthesis of novel chiral spiro-β-lactams from nitrile oxides and 6-()-(benzoylmethylene)penicillanate: batch, microwave-induced and continuous flow methodologies.

The first examples of the diastereoselective 1,3-dipolar cycloaddition reaction of nitrile oxides and 6-alkylidene penicillanates leading to chiral spiroisoxazoline-penicillanates are reported. The synthesis of this new type of penicillanate involved the selective generation of two consecutive stereogenic centers, including a quaternary chiral center. Furthermore, the present work also describes the outcomes of these 1,3-dipolar cycloaddition reactions under three distinct reaction conditions (conventional heating, microwave irradiation and continuous flow).

Unveiling a family of spiro-β-lactams with anti-HIV and antiplasmodial activity phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates.

The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC lower than 50 nM.

Insights into the anticancer activity of chiral alkylidene-β-lactams and alkylidene-γ-lactams: Synthesis and biological investigation.

Chiral alkylidene-β-lactams and alkylidene-γ-lactams were synthesized and screened for their in vitro activity against four human cancer cell lines (melanoma, esophageal, lung and fibrosarcoma carcinoma). Alkylidene-β-lactams were synthesized via Wittig reaction of diverse phosphorus ylides with benzhydryl 6-oxopenicillanate, derived from 6-aminopenicillanic acid. Moreover, novel chiral alkylidene-γ-lactams were synthesized through a multistep strategy starting from a chiral substrate (d-penicillamine).

Synthesis and structure-activity relationships of new chiral spiro-β-lactams highly active against HIV-1 and Plasmodium.

The synthesis and antimicrobial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information.

Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium.

The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and and no activity against bacteria and yeast.

Spiro-Lactams as Novel Antimicrobial Agents.

Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out.

Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity.

Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles.