Metal–antifungal drug complexes were investigated against fungus causing of sporotrichosis. They were more active against fungal cells than to mammalian cells.

No abstract

Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ‐gold(I) hybrid molecule affects essential parasite targets, it inhibits β‐hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ‐gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood‐stage of Plasmodium falciparum and liver‐stage of Plasmodium berghei and efficacy in vivo against P. berghei, thereby demonstrating its multiple‐stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.

No abstract

Hybrid-based drugs linked through a transition metal constitute an emerging concept for Plasmodium intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF6. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the Plasmodium life cycle. The source of this activity was thoroughly investigated by comparing parasite susceptibility to the hybrid’s components, the annotation of structure–activity relationships and studies of the mechanism of action. The activity of [AuAQPQ]PF6 for the parasite’s asexual blood stages was influenced by the presence of AQ, while its activity against gametocytes and pre-erythrocytic parasites was influenced by both quinolinic components. Moreover, the coordination of ligands to gold(I) was found to be essential for the enhancement of potency, as suggested by the observation that a combination of quinolinic ligands does not reproduce the antimalarial potency and efficacy as observed for the metallic hybrid. Our results indicate that this gold(I) hybrid compound presents a dual mechanism of action by inhibiting the beta-hematin formation and enzymatic activity of thioredoxin reductases. Overall, our findings support the potential of transition metals as a dual chemical linker and an antiplasmodial payload for the development of hybrid-based drugs.

A malária é um dos mais graves problemas de saúde publica no mundo, matando cerca de 435 mil pessoas em todo mundo a cada ano. Dessa forma, é necessária a busca por novas estratégias antimaláricas. Diante disso, neste trabalho é relatada a síntese de novos compostos, capazes de serem ativos contra cepas resistentes e, portanto, serem potencialmente utilizados na monoterapia da malária. Nesse sentido, foram descritas duas classes de novos complexos de ouro(I): os complexos metálicos híbridos e os complexos fosfínicos de ouro(I). Os híbridos de ouro(I) ([AuCQPQ]PF6 (1), [AuCQPQ]NO3 (2), [AuAQPQ]PF6 (3) e [AuAQPQ]NO3 (4)) foram obtidos empregando os precursores AuPQCl e [AuAQ2]Cl com o respectivo fármaco aminoquinolínico. Já os complexos fosfínicos de ouro(I) ([AuPQPPh3]NO3 (8), [AuPQPPh3]PF6 (9), [AuAQPPh3]NO3 (10) e [AuAQPPh3]PF6 (11)) foram alcançados por meio da reação entre o AuPPh3 com os fármacos antimaláricos primaquina e amodiaquina. Todos os complexos metálicos foram caracterizados por meio de técnicas analíticas e espectroscópicas, que compreendem: espectroscopia de absorção vibracional na região do infravermelho, espectroscopia de absorção eletrônica na região do UV-vis, análise elementar de C, H e N, RMN de 1H, 13C, COSY, DEPT 135, HMBC, HSQC, condutividade molar e ESI-MS. Os complexos híbridos pertencem a uma nova classe de compostos, onde uniu-se por meio do íon metálico ouro(I), dois fármacos que atuam em diferentes fases do ciclo do parasita (eritrocítico, sanguíneo e gametócitos), o que os torna potencialmente multi-fase. Cada componente da estrutura dos complexos híbridos de ouro(I) possui um potencial alvo biológico, o que também os torna promissores compostos multi-alvo. De fato, os resultados obtidos mostraram que os híbridos de ouro(I) exibiram uma interação reversível moderada com o DNA, que pode ser por intercalação ou interação com o sulco menor e também foram capazes de inibir a formação da β-hematina e a enzima TrxR, comprovando a capacidade multi-alvo dos híbridos 1 e 3. Os complexos metálicos híbridos (1 e 3) tiveram sua atividade antimalárica determinada por estudos in vitro, frente as cepas de P. falciparum sensíveis (3D7) e resitentes (W2) a cloroquina, e também por meio de estudos in vivo. O composto que mais se destacou frente aos estudos realizados foi o híbrido 3, que foi cerca de 100 vezes mais ativo que a cloroquina na cepa resistente. Os estudos in vivo constataram, que a utilização de complexos híbridos de ouro(I) pode ser melhor que a terapia combinada. Além disso, os compostos híbridos tiveram seu potencial multi-fase avaliado frente aos três estágios do ciclo do parasita (sanguíneo, hepático e dos gametócitos). Foi possível comprovar a ação multi-alvo e multi-fase dos híbridos 1 e 3. Finalmente, os compostos fosfínicos de ouro(I) tiveram seu mecanismo de ação avaliado frente a inibição da formação da β-hematina e observou-se que o composto 11 foi o que exibiu melhor capacidade de inibição.

No abstract

Quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II) and gold(I) containing amodiaquine (AQ) were synthesized and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline‐metal bond. Ru(II)‐ and Au(I)‐AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle assayed in vitro and in vivo. These properties could be attributed to the ability of the metal‐AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle, which can be attributed to the action of the metallic species. These findings indicate that metal coordination is a potential chemical tool for drug design and discovery in malaria.