Américo J. S. Alves

A computational framework predicts how abietic acid modifications influence polarity and compatibility, capturing subtle conformational effects such as pseudo‑amphiphilicity in long‑chain esters. Copilot assisted in creating the graphical

An unexplored reactivity of 6-(Z)-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-(Z)-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. Notably, one spiro-β-lactam exhibited excellent anti-HIV-1 activity.

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. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.

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.

This review gives an insight into the most recent synthetic methodologies towards spiro-γ-lactams, a class of compounds that are present in a wide range of synthetic bioactive and naturally occurring molecules.

The synthesis of a library of 6‐alkylidene‐β‐lactams, derived from 6‐aminopenicillanic acid is reported. The 1,3‐dipolar cycloaddition of these 6‐alkylidenepenicillanates with nitrones was explored as an approach to synthesize novel chiral spiroisoxazolidine‐β‐lactams. Quantum chemical calculations, at the DFT level of theory, were carried out to elucidate the 3D structure of the synthesized compounds. The reported methodology, which involves the generation of three new consecutive stereogenic centers, proved to be regio‐ and stereoselective, leading to novel chiral spiroisoxazolidine‐penicillanates efficiently.

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. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.

Furans have been explored as a scaffold for the synthesis of a range of heterocyclic compounds, exploring their dienophilic behaviour towards nitroso‐ and azoalkenes as the first step. Acid‐catalysed rearrangements of these cycloadducts, 4a,7a‐dihydro‐4H‐furo[2,3‐e][1,2]oxazines and 1,4,4a,7a‐tetrahydrofuro[3,2‐c]pyridazines, were studied. Using 1 equiv. of TFA, the bicyclic heterocycles derived from furan and 2‐methylfuran were converted into furans bearing side‐chains incorporating oxime and hydrazone groups by ring‐opening of the six‐membered ring with the concomitant aromatization of the furan ring. The use of TFA as solvent led to rearrangement via spirocyclic intermediates, followed by furan ring‐opening to afford functionalized isoxazoles or pyrazoles. Furthermore, furo‐oxazines derived from 2,5‐dimethylfuran, in which furan aromatization is precluded, were converted efficiently into 6H‐1,2‐oxazines through a furan ring‐opening reaction upon thermolysis in the presence of a catalytic amount of p‐toluenesulfonic acid. The tetrahydrofuro[3,2‐c]pyridazines derived from furan and dimethylfuran underwent acid‐catalysed addition reactions, leading to 6‐substituted hexahydrofuro[3,2‐c]pyridazines, when in the presence of alcohols or water.