Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.

Drug Candidates for Covid-19 Treatment in Brazil

Background: COVID-19 has emerged worldwide in less than 6 months, leaving millions of deaths behind. While scientist search for new drugs, an old arsenal has been proposed as a form of treatment. Objective: This article was designed as a literature review, scrutinizing antiparasitic chloroquine, ivermectin, nitazoxanide; and also glucocorticoids, as candidates to be applied in patients with COVID-19 in some Brazilian hospitals. Methodology: clinical evidence of COVID-infected patients and literature consultation have been accomplished for the construction of this article. On line searches and gray literature have also been consulted, whose database include PUBMED Central, BVS/BIREME, Web of Science, Science Direct, Higher Level Personnel Improvement Coordinator (CAPES), Periodic Door (Portal de Periódicos da CAPES, The Cochrane Library and PROSPERO). Results: chloroquine, ivermectin and nitazoxanide do present antiviral characteristics to support their usage in phase 1 of COVID-19 symptoms. Glucocorticoids, especially methylprednisolone and dexamethasone, seem to be efficient in patients with pulmonary symptoms, such as those present in phase 2B and 3 of the disease. Conclusion: After analyzing the literature, antiparasitic agents constitute a promising approach for patients with COVID-19. However, their usage seems to be efficient in the very beginning of the symptoms. Methylprednisolone and dexamethasone are best indicated for hospitalized patients with pulmonary commitment.

The Natural Compound Hydrophobic Usnic Acid and Hydrophilic Potassium Usnate Derivative: Applications and Comparisons

Usnic acid is the best-studied lichen metabolite, presenting several biological activities, such as antibacterial, immunostimulating, antiviral, antifungal, anti-inflammatory, and antiparasitic agents; despite these relevant properties, it is a hydrophobic and toxic molecule. In this context, scientific research has driven the development of innovative alternatives, considering usnic acid as a source of raw material in obtaining new molecules, allowing structural modifications (syntheses) from it. The purpose is to optimize biological activities and toxicity, with less concentration and/or response time. This work presents a literature review with an analogy of the hydrophobic molecule of usnic acid with its hydrophilic derivative of potassium usnate, emphasizing the elucidation and structural characteristics, biological activities, and toxicological aspects of both molecules, and the advantages of using the promising derivative hydrophilic in different in vitro and in vivo assays when compared to usnic acid.

CWHM-1008 Induces Apoptosis and Protective Autophagy through the Akt/mTOR Axis in LUAD Cells

Recent studies have revealed that antiparasitic agents showed promising inhibitory effects on tumors, raising a possibility that repositioning this class of drugs may shed new light on clinical therapy against tumors. CWHM-1008 is a novel class of antimalarial drug; however, the inhibitory impact of CWHM-1008 on lung adenocarcinoma (LUAD) cells remains unclear. This study aimed to explore the anticancer effect and underlying mechanisms of CWHM-1008 on LUAD cells in vitro and in vivo. Human LUAD cells, H358 and A549, were treated with varying concentrations of CWHM-1008 at different lengths of time. Cell viability, colony formation, cell count, flow cytometry findings, microtubule-associated protein-1 light chain 3-green- (LC3-) GFP/RFP adenovirus infection status, and the expression of apoptosis and autophagy-related proteins were examined. Potential effects of an autophagy inhibitor (LY294002) and constitutively active Akt plasmid (CA-Akt) on CWHM-1008-induced apoptosis were also examined. Our results showed that CWHM-1008 significantly inhibited proliferation, induced apoptosis, and enhanced autophagy flux by blocking the RAC-alpha serine/threonine-protein kinase/the mammalian target of rapamycin (Akt/mTOR) axis in two LUAD cells. In addition, autophagy inhibited by LY294002 or CA-Akt transfection accelerated CWHM-1008-induced apoptosis in those LUAD cells. Moreover, CWHM-1008 significantly inhibited the growth and induced apoptosis of A549 cell in nude mice in vivo. The present findings provide new insights into anticancer properties of CWHM-1008, suggesting that it may be an adjuvant treatment for LUAD treatment, warranting further study.

The role of antiparasitc drugs and steroids in Covid-19 treatment

Background: COVID-19 has emerged as a pandemic that spread throughout the world in less than 6 months, leaving hundred thousand deaths behind. Surprisingly, old drug arsenal has now been applied as an option of treatment. Objective: The aim of this article was to accomplish a literature review concerning the antiparasitic chloroquine, ivermectin, nitazoxanide; as well as glucocorticoids as possible therapeutic agents to be applied in patients with COVID-19 in Brazilian hospitals. Methodology: clinical evidence of COVID-infected patients and literature consultation have been used for the construction of this article. On line searches and gray literature have also been consulted, whose database include PUBMED Central, BVS/BIREME, Web of Science, Science Direct, Higher Level Personnel Improvement Coordinator (CAPES), Periodic Door (Portal de Periódicos da CAPES, The Cochrane Library and PROSPERO). Results: chloroquine, ivermectin and nitazoxanide present antiviral characteristics to support their usage in phase 1 of COVID-19 symptoms. Glucocorticoids such as methylprednisolone and dexamethasone seem to be more efficient in patients with pulmonary symptoms such as those in phase 2B and 3. Conclusion: According to the articles raised in this review, antiparasitic agents are promising for patients with COVID-19 in the very beginning of the symptoms. Methylprednisolone and dexamethasone are best indicated for hospitalized patients with pulmonary commitment.

Case Report: Refractory Cryptosporidiosis after CAR T-Cell Therapy for Lymphoma

Cryptosporidial diarrhea is uncommon in immunocompetent individuals, more often seen in severely immunocompromised patients. Severe refractory cases have been described in patients with HIV/AIDS before the advent of modern antiretroviral therapy due to an inability to mount an adequate cellular immune response. We describe an 85-year-old patient post–chimeric antigen receptor T-cell therapy relapsed lymphoma who developed refractory Cryptosporidium spp. diarrhea in the setting of persistent CD4+ cytopenia. Despite receiving multiple antiparasitic agents, including failure of a prolonged course of nitazoxanide, the patient experienced persistent symptoms for 9 months with repeatedly positivity stool Cryptosporidium spp. direct fluorescent antibody (DFA) test. We highlight this case of refractory Cryptosporidium spp. and the importance of recognizing the pathogen in a non–HIV-infected immunosuppressed host.

Patented technologies for schistosomiasis control and prevention filed by Chinese applicants

Background Many valuable and productive patented technologies have been developed to control schistosomiasis in China in the past 70 years. We conducted a research to analyse patented technologies for schistosomiasis control and prevention filed by Chinese applicants for determining the future patent layout. Methods The patent databases of China National Intellectual Property Administration and Baiten were comprehensively searched, and patented technologies for schistosomiasis control and prevention, published between January 1950 and December 2020 filed by Chinese applicants were sorted on 30 December 2020. The patent types, technical fields, and patent development trends were analysed using patent indexing. Results There are 184 valid schistosomiasis control technology patents, among them 128 invention patents. The patents related to schistosomiasis control and prevention technology have gone through the germination, growth, and maturity stages. These phases correspond with three phases in schistosomiasis control in China. The main technical aspects were fundamental research (n = 37), detection (n = 13), chemotherapy (n = 61), and armamentarium/devices (n = 73), of which the number of patents for detection for diagnosis was smaller. The top three specialised technical fields for patents subgroups, focusing on antiparasitic agents, DNA or RNA, vectors and medicines, of which schistosomicides are the major dominant subgroup. Conclusions We recommend that technologies to be patented for schistosomiasis control and prevention be focused on detection, preliminary studies for molecular detection methods should be significantly enhanced, and patent layout must be performed, which will, in turn, promote accuracy of early diagnosis, not only in humans but also in livestock. It is necessary to develop more anti-schistosomal drugs safely and effectively, exceptionally eco-friendly molluscicides and herbal extracts anti-schistosomes, improve treatment, develop vaccines for use in humans. Graphic abstract

Synthesis, Characterization and Evaluation of some newer Pyrimidine derivatives as Anti-inflammatory Agents

Pyrimidine is an important baseone of the base formed by hydrolysis of nucleosides. It is an interesting molecule in the medicinal chemistry because of its diversified biological activities. Alloxan which is an oxidation product of Uric acid is also a pyrimidine derivative of interest to a medicinal chemist. Several pyrimidines are reported as antimicrobial, analegesic, anti-inflammatory, antibacterial, and antiparasitic agents. Pyrimidine scaffold is considered as an interesting one due to its various pharmacological properties. In this scheme, an attempt is made to carry out synthesis of some new pyrimidine derivatives. The Starting material Chalcone is synthesized by condensation of various aromatic aldehyde and aromatic ketone. Chalcone is then treated with thiourea and KOH in presence of ethanol to yield pyrimidine derivatives. Then those pyrimidine derivatives were subjected to alkylation and acetylation. The synthesized compounds were characterized and confirmed by IR and 1HNMR spectroscopy and then evaluated for their anti-inflammatory activity. The anti-inflammatory activity of newly synthesized pyrimidine derivatives were carried out by the carrageenan induced rat hind paw edema method by taking Diclofenac sodium as standard.