Organocatalyzed stereospecific C-C bond formation of ß-lactams.

Herein, we report the development of mild, organocatalyzed routes to novel carbapenam derivatives through aldol, Mannich and Michael C-C bond forming reactions.

Cationic Chitosan Derivatives for the Inactivation of HIV-1 and SARS-CoV-2 Enveloped Viruses.

Cationic chitosan derivatives have been widely studied as potential antimicrobial agents. However, very little is known about their antiviral activity and mode of action against enveloped viruses. We investigated the ability of hydroxypropanoic acid-grafted chitosan (HPA-CS) and N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) to inactivate enveloped viruses like the human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane-disrupting potential of the chitosan derivatives was initially investigated in a hemolysis assay. At 1.0 mg/mL, about 80% hemolysis was observed for the cationic chitosan derivatives, which was significant when compared to almost no membrane-disrupting activity by the unmodified chitosan. Virus inhibition was evaluated using the luciferase-based antiviral assay against the HIV-1 NL4.3 virus (400 TCID). The IC50 of HPA-CS was 4.109 mg/mL, while the HTCC showed a higher antiviral activity at an IC50 = 0.225 mg/mL. For practical application, the antiviral efficacies of the HTCC-coated and uncoated nonmedical masks were evaluated for SARS- CoV-2 virus capture. The coated masks demonstrated an almost excellent performance with nearly 100% viral inhibition compared to less than 60% inhibition by the uncoated masks. Molecular docking predictions suggest that the HTCC polymers interact with the viral spike protein, blocking the coronavirus interaction with the target host cell's angiotensin-converting enzyme 2 cellular receptors.

A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria.

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.

Fluorinated Quaternary Chitosan Derivatives: Synthesis, Characterization, Antibacterial Activity, and Killing Kinetics.

Chitosan has become an established platform biopolymer with applications in biomedical engineering, nanomedicine, and the development of new materials with improved solubility, antimicrobial activity, and low toxicity. In this study, a series of chitosan derivatives were synthesized by conjugating various perfluorocarbon chains to chitosan via Schiff base formation or nucleophilic substitution, followed by quaternization with glycidyl trimethylammonium chloride to confer non-pH-dependent permanent positive charges. Synthesized fluorinated N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride polymers were characterized and investigated for their antibacterial efficacies against multidrug-resistant bacteria including clinical isolates. The polymers showed activity against both Gram-positive and Gram-negative bacteria (MIC = 64-512 µg/mL) but with greater potency against the former. They displayed rapid bactericidal properties, based on the MBC/MIC ratio, which were further confirmed by the time-kill kinetic assays. Given the properties presented here, fluorinated quaternary chitosan derivatives can serve as great candidates to be investigated as environmentally more benign, nontherapeutic antimicrobial agents that could serve as alternatives to the heavy reliance on antibiotics, which are currently in a very precarious state due to increasing occurrence of drug resistance.