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Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein, we describe the development of a novel class of 3-substituted benzoazepinedione derivatives with promising antibacterial activity. The pivotal compound, benzoazepinedione carboxylate 9, represents a highly electrophilic Michael acceptor, enabling divergent access to a wide range of thia-, aza-, oxa-, and phospha-Michael adducts. Notably, most prepared compounds exhibited potent antibacterial activity against both drug-susceptible and drug-resistant strains of Staphylococcus aureus (MIC 90 of up to 2 μg mL -1 ). The cytotoxicity assessment in the VERO6 cell line revealed that thia-adduct 10d (IC 50 of 36.5 μg mL -1 ) exhibits lower toxicity compared to its parent electrophile 9 (IC 50 of 14.3 μg mL -1 ), which is in agreement with the hypothesis of covalently modified prodrugs. Additionally, stability studies of the prepared compounds in CD 3 OD and a DMSO-PBS mixture confirmed that thia-Michael adducts 10 are stable under neutral conditions while dynamic under mildly basic conditions. Moreover, 3D reconstructed tissue models (human lung epithelial EpiAirway™ and a human small intestine model) did not exhibit a viability decrease below 80% of the untreated control at all concentrations tested, indicating tolerance to higher concentrations of potential drugs and prodrugs.

A metal-free, user-friendly photochemical transformation of nitroalkanes to oximes, nitrones, and hydroxylamines has been developed. The visible-light-induced reactions are catalyzed by the readily available photoredox organocatalyst 4CzIPN and use inexpensive amines as reductants. Broad in scope and tolerant of multiple functional groups and heterocycles, the transformation proceeds under mild conditions. Its synthetic potential was demonstrated in the formal total synthesis of amathaspiramide F. A basic insight into the reaction mechanism was gained with the help of an NMR study., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2 S ,4 S )-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by means of crystallization-induced diastereomer transformation (CIDT) in a highly stereoselective fashion. A Maillard-type condensation was crucial to constructing the desired pyrrolic scaffold.

Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a series of berkeleylactone A derivatives were synthesized and evaluated for their in vitro antimicrobial activities against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) strains. Our data confirmed the essential role of the embedded conjugated system and suggest a reversible sulfa-protection of the Michael acceptor as a viable option. Structurally simplified achiral macrolactam 8 showed the best inhibitory activity against S. aureus L12 (MRSA) with MIC 50 values of 0.39 μg mL -1 , 8-fold lower than those of berkeleylactone A. These studies may be of value in the development of more advanced candidates for antibiotic applications.

The first total synthesis of the potent antibiotic berkeleylactone A is described in 10 steps with an overall yield of 9.5%. A key step of our concise route is a late-stage, highly diastereoselective, sulfa-Michael addition. The 16-membered macrocyclic lactone was formed via ring closing metathesis and subsequent chemoselective reduction. The absolute stereochemical configuration was confirmed by single-crystal X-ray analysis. Synthetic berkeleylactone A was tested against several methicillin-resistant Staphylococcus aureus strains, and its potent antibacterial activity was verified.

Crystallization-induced diastereomer transformation (CIDT) represents a highly appealing and convenient synthetic tool. Despite its numerous advantages, it remains rather rarely used due to its uncertain predictability to occur. Herein, we describe CIDT based on aza-Michael reactions of diversely functionalized ( E)-3-acylacrylic acids. This method provides direct access to a broad variety of α-amino acid derivatives in excellent stereochemical purities.

The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3-d]pyrimidine 4'-C-methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4'-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di-O-acetyl-3,5-di-O-benzyl-4-C-methyl-β-d-ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus in a replicon assay.