Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium

Abstract

The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.

Unveiling a family of spiro-β-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates

“…methyl and ethyl ester) led to highly bioactive compounds 4 and 5 (IC 50 HIV-1 < 0.3 μM). A similar behavior was observed when the benzoyl group of BSS-730A (3) was replaced by a methyl ester in molecule BSS-722A (6), (Bártolo et al, 2021), although its replacement by a bulkier benzyl group lead to a total loss of activity (Alves et al, 2021c). In addition, similar to lead molecule BSS-730A (3), spirocyclopentene-β-lactams 4, 5 and BSS-722A (6) also display anti-Plasmodium activity.…”

“…Among the new chiral spiropenicillanates, spirocyclopenteneβ-lactam BSS-730A (3) stood out by presenting a bioactivity profile characterized by a nanomolar activity against both HIV-1 and HIV-2 (IC 50 HIV-1 = 0.014 μM and IC 50 HIV-2 = 0.008 μM, respectively), and a submicromolar activity against Plasmodium berghei hepatic infection (IC 50 = 0.550 μM) and Plasmodium falciparum erythrocytic infection (IC 50 = 0.430 μM) (Figure 2) (Bártolo et al, 2021). The antiviral target and mechanism of action of BSS-730A (3) remain elusive, as the compound has no HIV antiprotease activity and acts equally well against HIV whether it is added before or at different time-points after cell infection.…”

Broad Spectrum Functional Activity of Structurally Related Monoanionic Au(III) Bis(Dithiolene) Complexes

“…The HIV-1 SG3.1 subtype B strain was obtained by transfection of HEK293T cells with pSG3.1 plasmid using jetPrime transfection reagent (Polyplus-tranfection SA, Illkirch, France) according to the manufacturer's instructions. The 50% tissue culture infectious dose (TCID 50 ) of the virus was determined in a single-round viral infectivity assay using a luciferase reporter gene assay [90] in TZM-bl cells and calculated using the statistical method of Reed and Muench [91].…”

“…The antiviral activity of Auranofin, [P][AuSEt(=S)] and [P][AuSBu(=S)] compounds was determined in a single-round viral infectivity assay using TZM-bl reporter cells, as previously described [90]. Briefly, TZM-bl cells were infected with 200 TCID 50 of SG3.1 in the presence of serial-fold dilutions of the compounds in growth medium, supplemented with DEAE-dextran.…”

Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiro-β-lactam-isatin hybrids

“…antimalarial [14][15][16][17], antibacterial [18], antiviral [19], anti-HIV [14,15], antioxidant [20], anticancer and antiproliferative [20,21] activities. Moreover, spiro-β-lactams have been also used as synthons for synthesis of heterocycles and other organic compounds [22].…”