Improving the drug-likeness of inspiring natural products - evaluation of the antiparasitic activity against Trypanosoma cruzi through semi-synthetic and simplified analogues of licarin A

Abstract

Chagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi, endemic in Latin America and recently found in non-endemic countries of North America, Europe and Asia. The main form of transmission depends on the presence of a vector, being Triatoma infestans the most common 1. It is estimated that over eight million people are infected by the parasite and 70 million are at risk, living on endemic areas or in places where the control of other forms of transmission (oral, blood transfusion or organ transplant) is not rigid 2. CD is a two-stage disease: the acute phase, characterized by the high parasitaemia, and invasion by trypomastigote forms of different organs and the chronic phase, which may be latent for decades before appearance of clinical signs and usually associated with the development of cardiomyopathy 3,4. The available therapy for the treatment of CD is actually restricted to two approved drugs: benznidazole and nifurtimox, remains a controversial issue, with contradictory results in the chronic phase of the disease 5-8. Furthermore, these nitrocompounds showed several side effects associated to prolonged treatment regimens. Several clinical trials involving drug-repositioning (such as antifungal azoles) were carried out as well as studies involving new molecules, but none have reached the market yet 4. Therefore, new effective drugs for the treatment of CD are still needed. The Drugs for Neglected Diseases initiative (DNDi) defines that a desirable hit compound should present considerable efficacy (IC 50 < 10 µM), selectivity (>10-fold over mammalian cells) and adequate oral bioavailability 9. Natural products have always been a source of a great variety of bioactive molecules, mostly substances from the organism secondary metabolism. Many drugs available in the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products (semi-synthetic or completely synthetic) 10. The biodiversity of plants makes them a commonly explored source of novel bioactive compounds, providing molecules with distinct structures, complex or simple, with huge chemical variety 11. Several research groups are focused on the isolation and identification of novel compounds with antimicrobial activity from plant extracts, aiming to use them as prototypes for drug discovery against Chagas disease 12. In this context, licarin A is a neolignan isolated from different plant species with reported activity against Mycobacterium tuberculosis 13,14 , Schistosoma mansoni 15 , Trypanosoma cruzi 15-17 , and Leishmania major 18. Considering the promising activity against T. cruzi and the considerable amounts of licarin A isolated from the leaves of Nectandra oppositifolia (Lauraceae), this compound was selected for preparation of semi-synthetic analogues to further pharmacophore exploitation. Thereafter, licarin A was obtained in pure form and five semi-synthetic and twenty-one analogues were designed by the molecular simplification approach. The main objective wa...

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

“…This caveat provides the information showing that the administration of the Benznidazole to treat the T. cruzi infections is unsatisfactory. The information is in keeping with the observations stemmed from experimental protocols in animal models [144][145][146][147][148][149] and, accordingly, with the data obtained from human Chagas disease clinical trials [156][157][158][159][160][161][162], although the controversy remains [161][162][163][164][165][166][167][168][169]. In addition, the acutely infected mice permitted parasitemia for 10 days after the administration of Benznidazole + AZT + Ofloxacin.…”

Applications of Virtual Screening in Bioprospecting: Facts, Shifts, and Perspectives to Explore the Chemo-Structural Diversity of Natural Products

“…Natural products are chemically complex and differ from synthetic compounds in different aspects; as an example, these structures contain a high percentage of oxygen as well as a larger fraction of sp3-hybridized atoms and chiral centers (Lee and Schneider, 2001 ; Feher and Schmidt, 2003 ; Rodrigues et al, 2016 ), and their chemical space is highly diverse, containing different structural scaffolds, when compared with synthetic compound libraries (Chen et al, 2018 ). Due to their unique features, their structures can provide an innovative solution for the design and synthesis of new bioactive compounds (Kumar et al, 2017 ; Silva et al, 2019 ; Bradley et al, 2020 ; Morais et al, 2020 ).…”

Antiparasitic effect of stilbene and terphenyl compounds againstTrypanosoma cruziparasites

“…Therefore, natural products have always been a source of a great variety of bioactive molecules, mostly substances from the organism secondary metabolism. Many drugs available in the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products (semi-synthetic or completely synthetic) [4]. Recently, several natural and synthetic stilbene and terphenyl have been studied for their anticancer and leishmanicidal properties [5][6][7][8], in particular we evaluated the antileishmanial activity of two compounds, a trans-stilbene derivatives and a terphenyl derivatives, namely trans-1,3-dimethoxy-5-(4-methoxystyryl) benzene (ST18) and 3,4'',5trimethoxy-1,1':2',1''-terphenyl (TR4), presented the best activity and safety profiles [9,10].…”