Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is a promising drug target for novel antivirals against SARS-CoV-2. The marine natural product gallinamide A and several synthetic analogues were identified as potent inhibitors of cathepsin L with IC50 values in the picomolar range. Lead molecules possessed selectivity over other cathepsins and alternative host proteases involved in viral entry. Gallinamide A directly interacted with cathepsin L in cells and, together with two lead analogues, potently inhibited SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. Reduced antiviral activity was observed in cells overexpressing transmembrane protease, serine 2 (TMPRSS2); however, a synergistic improvement in antiviral activity was achieved when combined with a TMPRSS2 inhibitor. These data highlight the potential of cathepsin L as a COVID-19 drug target as well as the likely need to inhibit multiple routes of viral entry to achieve efficacy.

A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg −1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg −1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg −1 . ■ INTRODUCTIONMalaria is a mosquito-transmitted disease caused by parasites of the genus Plasmodium. 1 Almost half the global population lives in malaria endemic areas and is at high risk of infection. The most virulent human parasite is Plasmodium falciparum, which leads to a severe infection that is often deadly, especially for children. Each year there are over 200 million new cases of malaria, and in 2017, the disease was responsible for an estimated 435 000 deaths. 2 A major global health concern is that the currently employed drug regimens for malaria are rapidly losing their effectiveness due to the emergence of drugresistant parasites. Particularly concerning is the rapid emergence of resistance against the artemisinin (ART)-based combination therapies that serve as the cornerstone of antimalarial therapy. 2,3 The widespread resistance of Plasmodium against currently available drugs and the lack of an efficacious vaccine underscores the need for the development of novel antimalarials that operate through unique mechanisms of action. Many therapeutics in clinical use are either natural products or natural product derivatives. 4 The use of natural products as privileged biologically active scaffolds from which to develop new anti-infectives has proven to be a highly successful strategy, 5 e.g., in the development and clinical 49 approval of lipopeptide and glycopeptide antibiotic analogues 6 50 and antimalarial artemisinins. 7 51 We have recently explored analogues of gallinamide A (1), a 52 linear depsipeptide natural product isolated independently in 53 2009 from Schizothrix 8 and Symploca 9 species of cyanobacteria 54 f1 as antimalarial leads (Figure 1). 10 The natural product and 55 structural analogues have been shown to possess potent 56 inhibitory activity against P. falciparum growth in vitro. The 57 mechanism of action of these natural product analogues is due 58 to the inhibition of cysteine proteases, namely, falcipain 2 59 (FP2) and falcipain 3 (FP3), 11 which are critical for...

The Stevens rearrangement of a nitrile-stabilized ammonium ylide is the key step of a very short and practical synthesis of the phenanthroindolizine alkaloid (±)-tylophorine. The method requires only five linear steps and is devoid of any protecting group manipulations.

An animalic note: The first total synthesis of the all-cis nupharamine 2, an alkaloid from beaver castoreum, is based on the stereoselective domino Mannich-Michael reaction of N-galactosylfurylaldimine to give 1 (Piv = pivaloyl), subsequent conjugate cuprate addition, and stereoselective protonation of the enolate. These reactions are all controlled by the carbohydrate. Protonation of the enolate after cleavage of the auxiliary leads to epimer 3.

The phenanthroindolizidine alkaloid (S)-(+)-tylophorine was synthesized from L-proline in nine linear steps including a double bromination and a free-radical cyclization of an N-aziridinylimine as the key steps. The phenanthrene moiety was prepared from homoveratric acid and veratraldehyde and permits the variation of each oxygen-substituted ring.