Carlos H. Escalantea

In this work, we report a concise, protecting-group-free, seven-step total synthesis of (±)-mersicarpine in 15% overall yield, from commercial γ-caprolactone, representing the shortest racemic route reported to date. In addition, formal synthetic approaches to rhazinilam and leuconoxine alkaloids were achieved. The strategy relies on a cyanomethyl radical cascade cyclization of N-alkene-linked indole and pyrrole substrates under either DLP-mediated or photoredox conditions, providing rapid access to key polycyclic frameworks.

This paper describes an efficient strategy that uses a Michael/lactamization/Michael one-pot cascade process to construct the pentacyclic core of tronocarpine. This key transformation used a seven-membered lactam derived from tryptamine and a Michael double acceptor to produce an advanced intermediate with all of the necessary functional groups to synthesize the natural product in 53% yield. Dihydrotronocarpine was then synthesized from this intermediate in two additional steps.

An acid-catalyzed regioselective addition of diverse nucleophiles to exo-oxazolidin-2-one dienes was presently carried out, leading to a series of functionalized 4-oxazolin-2-ones. The direct formylation of 4-methyl-4-oxazolin-2-ones provided the corresponding 5-formyl-4-oxazolin-2-ones, which were applied in the construction of the 4,5-dihydrobenzo[d]oxazolones through a Staunton-Weinreb annulation process. The reactivity of symmetrical and unsymmetrical exo-imidazolidin-2-one dienes was studied in Diels–Alder cycloadditions with dienophiles N-phenylmaleimide and benzyne. The aromatization of the [4+2] adducts led to the polycyclic benzo- and naphtho[d]imidazol-2-ones, which have potential pharmacological activity. Resumen. Se describe la adición regioselectiva catalizada por ácido de diversos nucleófilos a los dienos exo-oxazolidinonas que conduce a una serie de 4-oxazolin-2-onas funcionalizadas. La formilación directa de 4-metil-4-oxazolidin-2-onas proporcionó las 5-formil-4-oxazolin-2-onas correspondientes, las cuales se emplearon en la construcción de las 4,5-dihidrobenzo[d]oxazolonas mediante un proceso de anillación de Staunton-Weinreb. Se estudió la reactividad de dienos exo-imidazolidin-2-onas simétricos y no simétricos en cicloadiciones de Diels-Alder con los dienófilos N-fenilmaleimida y bencino. La aromatización de los aductos [4+2] condujo a los benzo- y nafto[d]imidazol-2-onas policíclicas como compuestos con actividad farmacológica potencial.

A one-pot reaction of methyl N -aryl and N -benzylglycinates with isocyanates and DMFDMA led to 5-(dimethylamino)methylene hydantoins, which were converted into oxoaplysinopsines and parabanic acids. These compounds exhibit a high antifungal activity.

The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K₂CO₃ or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs.

As a new approach, pyrrolo[1,2-a]pyrazines were synthesized through the cyclization of 2-formylpyrrole-based enaminones in the presence of ammonium acetate. The enaminones were prepared with a straightforward method, reacting the corresponding alkyl 2-(2-formyl-1H-pyrrol-1-yl)acetates, 2-(2-formyl-1H-pyrrol-1-yl)acetonitrile, and 2-(2-formyl-1H-pyrrol-1-yl)acetophenones with DMFDMA. Analogous enaminones elaborated from alkyl (E)-3-(1H-pyrrol-2-yl)acrylates were treated with a Lewis acid to afford indolizines. The antifungal activity of the series of substituted pyrroles, pyrrole-based enaminones, pyrrolo[1,2-a]pyrazines, and indolizines was evaluated on six Candida spp., including two multidrug-resistant ones. Compared to the reference drugs, most test compounds produced a more robust antifungal effect. Docking analysis suggests that the inhibition of yeast growth was probably mediated by the interaction of the compounds with the catalytic site of HMGR of the Candida species.

Current antidiabetic drugs have severe side effects, which may be minimized by new selective molecules that strongly inhibit α-glucosidase and weakly inhibit α-amylase. We have synthesized novel alkoxy-substituted xanthones and imidazole-substituted xanthones and have evaluated them for their in silico and in vitro α-glucosidase and α-amylase inhibition activity. Compounds 6c, 6e, and 9b promoted higher α-glucosidase inhibition (IC₅₀ = 16.0, 12.8, and 4.0 µM, respectively) and lower α-amylase inhibition (IC₅₀ = 76.7, 68.1, and >200 µM, respectively) compared to acarbose (IC₅₀ = 306.7 µM for α-glucosidase and 20.0 µM for α-amylase). Contrarily, derivatives 10c and 10f showed higher α-amylase inhibition (IC₅₀ = 5.4 and 8.7 µM, respectively) and lower α-glucosidase inhibition (IC₅₀ = 232.7 and 145.2 µM, respectively). According to the structure–activity relationship, attaching 4-bromobutoxy or 4′-chlorophenylacetophenone moieties to the 2-hydroxy group of xanthone provides higher α-glucosidase inhibition and lower α-amylase inhibition. In silico studies suggest that these scaffolds are key in the activity and interaction of xanthone derivatives. Enzymatic kinetics studies showed that 6c, 9b, and 10c are mainly mixed inhibitors on α-glucosidase and α-amylase. In addition, drug prediction and ADMET studies support that compounds 6c, 9b, and 10c are candidates with antidiabetic potential.

Palladium-catalyzed functionalization was presently performed on two building blocks: 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones. Direct Heck arylation of 4-oxazolin-2-ones led to a series of 5-aryl-4-oxazolin-2-ones, including analogues with N-chiral auxiliary, in an almost quantitative yield. The Pd(II)-catalyzed homocoupling reaction of 4-oxazolin-2-ones provided novel heterocyclic across-ring dienes. Meanwhile, the intramolecular cross-coupling of N-aryl-4-methylene-2-oxazolidinones furnished a series of oxazolo[3,4-a]indol-3-ones. Further functionalization of 4-methylene-2-oxazolidinones afforded substituted indoles and heterocyclic-fused indoles with aryl, bromo, carbinol, formyl, and vinyl groups. A computational study was carried out to account for the behavior of the formylated derivatives. The currently developed methodology was applied to a new formal total synthesis of ellipticine.

New and efficient strategies for the conversion of 4‐oxazolin‐2‐ones into 1‐methyl and 1,4‐dimethyl 3‐formylcarbazoles are herein described. Highly convergent cascade and one‐pot processes afforded the corresponding diarylamines, as in situ formed synthetic intermediates or final products in high overall yields. Special attention was given to the synthesis of methylated carbazoles by reacting 4,5‐dimethyl‐4‐oxazolin‐2‐ones with enones under microwave irradiation. The carbazole scaffold was provided by the palladium(II)‐catalyzed double C−H activation to generate oxidative cyclization of diarylamines. This methodology allowed for formal total syntheses of four naturally occurring pyrido[4,3‐b]carbazole alkaloids ellipticine, 9‐methoxyellipticine, olivacine, and 9‐methoxyolivacine.

Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris , Candida glabrata , and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals.