RESUMO
In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 µM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.
Assuntos
Antimaláricos/farmacologia , Ascomicetos/química , Isocumarinas/farmacologia , Animais , Antozoários/microbiologia , Antimaláricos/síntese química , Organismos Aquáticos/química , China , Chlorocebus aethiops , DNA Girase , Hemeproteínas , Isocumarinas/síntese química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacologia , Células VeroRESUMO
Identification and analysis of the whole genome of the marine-derived fungus Penicillium brasilianum HBU-136 revealed the presence of an interesting biosynthetic gene cluster (BGC) for non-ribosomal peptide synthetases (NRPS), highly homologous to the BGCs of indole-diketopiperazine derivatives. With the aid of genomic analysis, eight indole-diketopiperazines (1-8), including three new compounds, spirotryprostatin G (1), and cyclotryprostatins F and G (2 and 3), were obtained by large-scale cultivation of the fungal strain HBU-136 using rice medium with 1.0% MgCl2. The absolute configurations of 1-3 were determined by comparison of their experimental electronic circular dichroism (ECD) with calculated ECD spectra. Selective cytotoxicities were observed for compounds 1 and 4 against HL-60 cell line with the IC50 values of 6.0 and 7.9 µM, respectively, whereas 2, 3, and 5 against MCF-7 cell line with the IC50 values of 7.6, 10.8, and 5.1 µM, respectively.
Assuntos
Organismos Aquáticos/química , Dicetopiperazinas/química , Fungos/química , Fungos/genética , Indóis/química , Penicillium/química , Penicillium/genética , Organismos Aquáticos/genética , Linhagem Celular Tumoral , Dicroísmo Circular , Genoma/genética , Genômica , Células HL-60 , Humanos , Células MCF-7 , Família Multigênica/genética , Peptídeo Sintases/genéticaRESUMO
Tuberculosis has been one of the greatest global health challenges of all time. Although the current first-line anti-tuberculosis (anti-TB) medicines used in the clinic have reduced mortality, multidrug-resistance and extensively drug-resistance forms of the disease have now spread worldwide and become a global problem. Even so, few new clinically approved drugs have emerged during the past 30 years. Highly biodiverse marine organisms have received considerable attention for drug discovery in the past couple of decades, and emerging TB drug resistance has motivated interest in assessing marine natural products (MNPs) in the treatment of this disease. So far, more than 170 compounds have been isolated from marine organisms with anti-TB properties, ten of which exhibit potent activity and have the potential for further development. This review systematically surveys MNPs with anti-TB activity and illustrates the impact of these compounds on drug discovery research against tuberculosis.