Synthesis of novel aminoquinolines with potential leishmanicidal and antimalarial biological activity / Síntese de novas aminoquinolinas com potencial actividade biológica leishmanicida e antimalárica

Leishmaniasis is a disease transmitted by different parasite species of the genus Leishmania, while malaria, by protozoa of the genus Plasmodium sp. These diseases affect tropical and subtropical regions, where about half of the world's population live. However, leishmaniasis and malaria are considered neglected diseases because these regions are poor, and consequently have precarious essential sanitation networks. In response to the lack of vaccines and effective medical measures, some natural and synthetic medicines are used as forms of treatment, such as quinoline derivatives necessary to treat malaria. Even so, the parasites have shown resistance to forms of treatment, which makes needed the constant development of new drugs with potential against them. Quinoline derivatives, chloroquine analogues, have potential activity for the diseases of interest, while anilines are molecules used in nucleophilic reactions on different substrates. Therefore, the work consisted of exploring the synthesis between these two compounds through subsequent reactions involving the formation of intermediates that resulted in the products of interest. Twelve novel derivatives with potential leishmanicidal and antimalarial biological activity were synthesized. The molecules produced were purified and rightly characterized by several methods, such as mass spectrometry, infrared spectroscopy, and Nuclear Magnetic Resonance of Carbon (13C) and Hydrogen (1H). Also, were obtained the melting points of the synthesized molecules. Finally, all products were sent for biological tests against the parasites, getting highly effective results for the protozoa responsible for leishmaniasis.

Identification of Suitable Agents against Adenine Phosphoribosyl Transferase for the Management of Leishmaniasis: Synthesis, Characterization and Computational Studies

A leishmaniasis is a group of diseases attributable to protozoan parasites of the genus Leishmania. It is a potential disease mostly occurring in developing nations. Various quinoline substituted derivatives (11a-f, 12a-f, and 13a-f) were synthesized by refluxing amino quinolines with an equivalent number of different alkylaminoethyl chlorides and evaluated for their in vitro antileishmanial activity against promastigotes forms of Leishmania donovani by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] reduction assay. Compounds 11f (IC50 = 13.61μg/mL), 12f (IC50 = 11.92 μg/mL) and 13f (IC50 =10.41 μg/mL) have shown significant antileishmanial activity when compared with standard sitamaquine (IC50= 10.09 μg/mL). Furthermore, the molecular docking analysis targeting adenine phosphoribosyltransferase of Leishmania donovani exhibits significant binding interactions. In silico, ADMET predictions revealed that these compounds, i.e., 11f, 12f, and 13f, demonstrated good absorption as well as solubility characteristics with good drug-likeness and drug score values compared to the standard drug.

Seasonal dynamics of Phlebotomus Papatasi (Scopoli, 1786) (Diptera: Psychodidae) population in southern Republic of Moldova

Phlebotomine sand flies are vectors of several infectious pathogens, including parasitic protozoans of the genus Leishmania and phleboviruses. Increasing sand fly biting nuisance reported by residents from southern Republic of Moldova since 2011 initiated this study. Ceadir-Lunga, a semi-urban locality in southern Republic of Moldova was selected for seasonal sand fly collections outdoors and indoors in 2015 and 2017 using CDC light traps and manual aspirators. Continuous trapping showed markedly longer activity of P. papatasi indoors. Specimens were collected from first aspirations in the second half of June until last collections in mid-September, suggesting that the actual indoor activity of P. papatasi may have been longer. Low numbers of trapped specimens do not allow make accurate conclusions regarding the seasonal dynamics.

The First Record of Zoonotic Genes of Cutaneous Leishmaniasis among Human, Dogs, and Sandflies by Nested Polymerase Chain Reaction and Phylogenetic Analyses

Cutaneous leishmaniasis (CL) is one of the zoonotic diseases that is caused by protozoa of the genus Leishmania. The study aimed to diagnosed CL in human, dogs, and sandflies by PCR, and identification the zoonotic gene of CL by the nested PCR technique. A total of 100 patients with CL, 237 of owned-dogs, and 147 females sandflies collected. (88%) of humans samples, (95.77% skin biopsies and 20.69% of blood samples) of dogs, and (40.58%) of sandflies tissues were positive for L. major, while L. tropica infection was positive in (12%) of humans, in (4.23% symptomatic, and 6.89% asymptomatic) of dogs, and in (27.54%) of sandflies samples. The sequence ID of the local L. major in human were registered in NCBI as (MW421598.1, MW421599.1, MW421600.1), in dogs (MW421601.1, MW421602.1, MW421603.1), and sandflies (MW421604.1, MW421605.1, MW421606.1). While L. tropica in human were registered in NCBI as (MW421604.1, MW421605.1, MW421606.1), in dogs (MW421428.1, MW421429.1), and in sandflies (MW421430.1, MW421431.1). To our knowledge, this is the first study that contributes to the diagnosis of CL spp. in three different hosts (human, dogs, and sandflies) at the same time, particularly in Iraq and in Middle East countries.

CYTOLOGICAL DIAGNOSIS OF LEISHMANIAL LYMPHADENITIS

Leishmaniasis is a chronic inammatory disease caused by obligate intracellular kinetoplast containing parasite of the genus Leishmania. Leishmaniasis produces varied group of clinical syndromes ranging from self-healing cutaneous ulceration to fatal visceral disease. In India it is endemic in Bihar, Sub-Himalayan regions and other north Indian states. We present a rare Cytology case of Leishmaniasis in a young boy, hailing from a non-endemic area, presenting as Isolated Inguinal Lymphadenopathy.

The Maze Pathway of Coevolution: A Critical Review over the Leishmania and Its Endosymbiotic History

The description of the genus Leishmania as the causative agent of leishmaniasis occurred in the modern age. However, evolutionary studies suggest that the origin of Leishmania can be traced back to the Mesozoic era. Subsequently, during its evolutionary process, it achieved worldwide dispersion predating the breakup of the Gondwana supercontinent. It is assumed that this parasite evolved from monoxenic Trypanosomatidae. Phylogenetic studies locate dixenous Leishmania in a well-supported clade, in the recently named subfamily Leishmaniinae, which also includes monoxenous trypanosomatids. Virus-like particles have been reported in many species of this family. To date, several Leishmania species have been reported to be infected by Leishmania RNA virus (LRV) and Leishbunyavirus (LBV). Since the first descriptions of LRVs decades ago, differences in their genomic structures have been highlighted, leading to the designation of LRV1 in L. (Viannia) species and LRV2 in L. (Leishmania) species. There are strong indications that viruses that infect Leishmania spp. have the ability to enhance parasitic survival in humans as well as in experimental infections, through highly complex and specialized mechanisms. Phylogenetic analyses of these viruses have shown that their genomic differences correlate with the parasite species infected, suggesting a coevolutionary process. Herein, we will explore what has been described in the literature regarding the relationship between Leishmania and endosymbiotic Leishmania viruses and what is known about this association that could contribute to discussions about the worldwide dispersion of Leishmania.

Effects of Visceralising Leishmania on the Spleen, Liver, and Bone Marrow: A Pathophysiological Perspective

The leishmaniases constitute a group of parasitic diseases caused by species of the protozoan genus Leishmania. In humans it can present different clinical manifestations and are usually classified as cutaneous, mucocutaneous, and visceral (VL). Although the full range of parasite—host interactions remains unclear, recent advances are improving our comprehension of VL pathophysiology. In this review we explore the differences in VL immunobiology between the liver and the spleen, leading to contrasting infection outcomes in the two organs, specifically clearance of the parasite in the liver and failure of the spleen to contain the infection. Based on parasite biology and the mammalian immune response, we describe how hypoxia-inducible factor 1 (HIF1) and the PI3K/Akt pathway function as major determinants of the observed immune failure. We also summarize existing knowledge on pancytopenia in VL, as a direct effect of the parasite on bone marrow health and regenerative capacity. Finally, we speculate on the possible effect that manipulation by the parasite of the PI3K/Akt/HIF1 axis may have on the myelodysplastic (MDS) features observed in VL.

Retrospective study of american cutaneous leishmaniosis in humans in the city of Manaus, Amazonas (2018-2019)

American Tegumentary Leishmaniasis (ATL) is characterized as a zoonosis caused by protozoa of the genus Leishmania spp., presenting a chronic, non-contagious evolution, and its transmission occurs through the bite of sand fly insects (Diptera: Psychodidae). The process of expansion of cities, agricultural frontiers, and the occupation of peripheral areas contribute to the occurrence of epidemic outbreaks of the disease. This article aimed to study the incidence of human cases of ATL in the city of Manaus, describing qualitatively and quantitatively the occurrence of this disease. From the transfer of data from the Notifiable Diseases Information System - SINAN, made available by the Amazonas Health Surveillance Foundation - FVS/AM, this study describes a total of 789 cases, which occurred between 2018 and 2019, in the capital of Amazonas, which were classified according to age, gender, occupation, clinical signs, as well as the condition of the autochthonous case, the relationship with work, and the evolution of the case. As a result, 789 cases were confirmed, ranging in age from 1 to 90 years, and with a higher prevalence in males. As for the form of the lesion, the cutaneous type was identified in 98.73% of the cases, and 57% of the cases had a clinical cure. The results show ATL as a disease related to the socioeconomic and mainly health conditions in which the patient fits, with a high number of patients in large expanding cities, such as the city of Manaus. Thus, further work is needed to provide clarification on the disease, especially in the state of Amazonas, as it is still a neglected disease and related to the population's living conditions.

Insights into Leishmania Molecules and Their Potential Contribution to the Virulence of the Parasite

Neglected parasitic diseases affect millions of people worldwide, resulting in high morbidity and mortality. Among other parasitic diseases, leishmaniasis remains an important public health problem caused by the protozoa of the genus Leishmania, transmitted by the bite of the female sand fly. The disease has also been linked to tropical and subtropical regions, in addition to being an endemic disease in many areas around the world, including the Mediterranean basin and South America. Although recent years have witnessed marked advances in Leishmania-related research in various directions, many issues have yet to be elucidated. The intention of the present review is to give an overview of the major virulence factors contributing to the pathogenicity of the parasite. We aimed to provide a concise picture of the factors influencing the reaction of the parasite in its host that might help to develop novel chemotherapeutic and vaccine strategies.

Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise

Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans worldwide. Because a vaccine is not available and the currently small number of existing drugs are less than ideal due to lack of specificity and emerging drug resistance, the need for new therapeutic strategies is urgent. Natural products and their derivatives are being used and explored as therapeutics and interest in developing such products as antileishmanials is high. The enzyme arginase, the first enzyme of the polyamine biosynthetic pathway in Leishmania, has emerged as a potential therapeutic target. The flavonols quercetin and fisetin, green tea flavanols such as catechin (C), epicatechin (EC), epicatechin gallate (ECG), and epigallocatechin-3-gallate (EGCG), and cinnamic acid derivates such as caffeic acid inhibit the leishmanial enzyme and modulate the host’s immune response toward parasite defense while showing little toxicity to the host. Quercetin, EGCG, gallic acid, caffeic acid, and rosmarinic acid have proven to be effective against Leishmania in rodent infectivity studies. Here, we review research on these natural products with a focus on their promise for the development of treatment strategies as well as unique structural and pharmacokinetic/pharmacodynamic features of the most promising agents.