Natural and synthetic molecules with potential to enhance biofilm formation and virulence properties in Pseudomonas aeruginosa.

Pseudomonas aeruginosa can efficiently adapt to changing environmental conditions due to its ubiquitous nature, intrinsic/acquired/adaptive resistance mechanisms, high metabolic versatility, and the production of numerous virulence factors. As a result, P. aeruginosa becomes an opportunistic pathogen, causing chronic infection in the lungs and several organs of patients suffering from cystic fibrosis. Biofilm established by P. aeruginosa in host tissues and medical device surfaces has been identified as a major obstruction to antimicrobial therapy. P. aeruginosa is very likely to be closely associated with the various microorganisms in the host tissues or organs in a pathogenic or nonpathogenic behavior. Aside from host-derived molecules, other beneficial and pathogenic microorganisms produce a diverse range of secondary metabolites that either directly or indirectly favor the persistence of P. aeruginosa. Thus, it is critical to understand how P. aeruginosa interacts with different molecules and ions in the host and abiotic environment to produce extracellular polymeric substances and virulence factors. Thus, the current review discusses how various natural and synthetic molecules in the environment induce biofilm formation and the production of multiple virulence factors.

An update on the development of antiviral against Mayaro virus: from molecules to potential viral targets.

Mayaro virus (MAYV), first isolated in 1954 in Trinidad and Tobago islands, is the causative agent of Mayaro fever, a disease characterized by fever, rashes, headaches, myalgia, and arthralgia. The infection can progress to a chronic condition in over 50% of cases, with persistent arthralgia, which can lead to the disability of the infected individuals. MAYV is mainly transmitted through the bite of the female Haemagogus spp. mosquito genus. However, studies demonstrate that Aedes aegypti is also a vector, contributing to the spread of MAYV beyond endemic areas, given the vast geographical distribution of the mosquito. Besides, the similarity of antigenic sites with other Alphavirus complicates the diagnoses of MAYV, contributing to underreporting of the disease. Nowadays, there are no antiviral drugs available to treat infected patients, being the clinical management based on analgesics and non-steroidal anti-inflammatory drugs. In this context, this review aims to summarize compounds that have demonstrated antiviral activity against MAYV in vitro, as well as discuss the potentiality of viral proteins as targets for the development of antiviral drugs against MAYV. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential anti-MAYV drug candidates.

Insights into enterovirus a-71 antiviral development: from natural sources to synthetic nanoparticles.

Enteroviruses are pathogens responsible for several diseases, being enterovirus A71 (EVA71) the second leading cause of hand, foot, and mouth disease (HFMD), especially in Asia-Pacific countries. HFMD is mostly common in infants and children, with mild symptoms. However, the disease can result in severe nervous system disorders in children as well as in immunosuppressed adults. The virus is highly contagious, and its transmission occurs via fecal-oral, oropharyngeal secretions, and fomites. The EVA71 burdens the healthy systems and economies around the world, however, up to date, there is no antiviral approved to treat infected individuals and the existent vaccines are not available or approved to be used worldwide. In this context, an extensive literature research was conducted to describe and summarize the recent advances in natural and/or synthetic compounds with antiviral activity against EVA71. The summarized data presented here might simply encourage the future studies in EVA71 antiviral development, by encouraging further research encompassing these compounds or even the application of the techniques and technologies to improve or produce new antiviral molecules.

Activity of compounds derived from benzofuroxan in Trichomonasvaginalis.

Trichomoniasis is a sexually transmitted infection caused by the protozoan Trichomonas vaginalis. Currently, trichomoniasis is treated with the class of nitroimidazoles, namely, metronidazole; however, resistant isolates and strains have been reported. The compounds derived from benzofuroxan are biologically active heterocycles. This study evaluated the in vitro antiparasitic activity of these compounds in trophozoites of T. vaginalis and determined the mean inhibitory concentration (IC50), minimum inhibitory concentration (MIC), mortality curve, and cytotoxicity. The compounds were named EH1, EH2, EH3, and EA2 and tested in various concentrations: 100 to 15 µM (EH1 and EH2); 100 to 5 µM (EH3); and 100 to 25 µM (EA2), respectively. The greatest efficacy was observed in the highest concentrations in 24 h, with inhibition of approximately 100% of trophozoites. Compounds EH2 and EH3 had the lowest MIC: EH2 (35 µM) and EH3 (45 µM), with IC50 of 11.33 µM and 6.83 µM, respectively. Compound EA2 was effective at the highest concentrations. The activity of the compounds in T. vaginalis started in the first hour of incubation with 90% inhibition; after 12 h, inhibition >95% was observed. Compound EH1 showed the lowest activity, with the highest activity between 12 and 24 h after incubation. These results demonstrate that benzofuroxan derivatives are promising compounds for the in vitro treatment of T. vaginalis.

Therapeutic Effects of Curcumin Derivatives against Obesity and Associated Metabolic Complications: A Review of In Vitro and In Vivo Studies.

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

The Role of Natural and Semi-Synthetic Compounds in Ovarian Cancer: Updates on Mechanisms of Action, Current Trends and Perspectives.

Ovarian cancer represents a major health concern for the female population: there is no obvious cause, it is frequently misdiagnosed, and it is characterized by a poor prognosis. Additionally, patients are inclined to recurrences because of metastasis and poor treatment tolerance. Combining innovative therapeutic techniques with established approaches can aid in improving treatment outcomes. Because of their multi-target actions, long application history, and widespread availability, natural compounds have particular advantages in this connection. Thus, effective therapeutic alternatives with improved patient tolerance hopefully can be identified within the world of natural and nature-derived products. Moreover, natural compounds are generally perceived to have more limited adverse effects on healthy cells or tissues, suggesting their potential role as valid treatment alternatives. In general, the anticancer mechanisms of such molecules are connected to the reduction of cell proliferation and metastasis, autophagy stimulation and improved response to chemotherapeutics. This review aims at discussing the mechanistic insights and possible targets of natural compounds against ovarian cancer, from the perspective of medicinal chemists. In addition, an overview of the pharmacology of natural products studied to date for their potential application towards ovarian cancer models is presented. The chemical aspects as well as available bioactivity data are discussed and commented on, with particular attention to the underlying molecular mechanism(s).

A systematic review of synthetic tyrosinase inhibitors and their structure-activity relationship.

Tyrosinase is a copper-containing oxidation enzyme, which is responsible for the production of melanin. This enzyme is widely distributed in microorganisms, animals and plants, and plays an essential role in undesirable browning of fruits and vegetables, antibiotic resistance, skin pigment formation, sclerotization of cuticle, neurodegeneration, etc. Hence, it has been recognized as a therapeutic target for the development of antibrowning agents, antibacterial agents, skin-whitening agents, insecticides, and other therapeutic agents. With great potential application in food, agricultural, cosmetic and pharmaceutical industries, a large number of synthetic tyrosinase inhibitors have been widely reported in recent years. In this review, we systematically summarized the advances of synthetic tyrosinase inhibitors in the literatures, including their inhibitory activity, cytotoxicity, structure-activity relationship (SAR), inhibition kinetics, and interaction mechanisms with the enzyme. The collected information is expected to provide a rational guidance and effective strategy to develop novel, potent and safe tyrosinase inhibitors for better practical applications in the future.

In vitro and in silico trichomonacidal activity of 2,8-bis(trifluoromethyl) quinoline analogs against Trichomonas vaginalis.

Trichomoniasis is a great public health burden worldwide and the increase in treatment failures has led to a need for finding alternative molecules to treat this disease. In this study, we present in vitro and in silico analyses of two 2,8-bis(trifluoromethyl) quinolines (QDA-1 and QDA-2) against Trichomonas vaginalis. For in vitro trichomonacidal activity, up to seven different concentrations of these drugs were tested. Molecular docking, biochemical, and cytotoxicity analyses were performed to evaluate the selectivity profile. QDA-1 displayed a significant effect, completely reducing trophozoites viability at 160 µM, with an IC50 of 113.8 µM, while QDA-2 at the highest concentration reduced viability by 76.9%. QDA-1 completely inhibited T. vaginalis growth and increased reactive oxygen species production and lipid peroxidation after 24 h of treatment, but nitric oxide accumulation was not observed. In addition, molecular docking studies showed that QDA-1 has a favorable binding mode in the active site of the T. vaginalis enzymes purine nucleoside phosphorylase, lactate dehydrogenase, triosephosphate isomerase, and thioredoxin reductase. Moreover, QDA-1 presented a level of cytotoxicity by reducing 36.7% of Vero cells' viability at 200 µM with a CC50 of 247.4 µM and a modest selectivity index. In summary, the results revealed that QDA-1 had a significant anti-T. vaginalis activity. Although QDA-1 had detectable cytotoxicity, the concentration needed to eliminate T. vaginalis trophozoites is lower than the CC50 encouraging further studies of this compound as a trichomonacidal agent.

Regulation of Myeloid Dendritic Cells by Synthetic and Natural Compounds for the Treatment of Rheumatoid Arthritis.

Different subsets of dendritic cells (DCs) participate in the development of rheumatoid arthritis (RA). In particular, myeloid DCs play a key role in the generation of autoreactive T and B cells. Herein, we undertook a literature review on those synthetic and natural compounds that have therapeutic efficacy/potential for RA and act through the regulation of myeloid DCs. Most of these compounds inhibit both the maturation of DCs and their secretion of inflammatory cytokines and, subsequently, alter the downstream T-cell response (suppression of Th1 and Th17 responses while expanding the Treg response). The majority of the synthetic compounds are approved for the treatment of patients with RA, which is consistent with the importance of DCs in the pathogenesis of RA. All of the natural compounds are derived from plants. Their DC-modulating effect has been demonstrated both in vitro and in vivo. In addition, these natural products ameliorate arthritis in rodents and are potential therapeutics for human RA.

Evaluation of Anticancer and Antibacterial Activity of Four 4-Thiazolidinone-Based Derivatives.

Heterocycles are commonly known for their unique features, e.g., antibacterial or anticancer properties. Although many synthetic heterocycles, such as 4-thiazolidinone (4-TZD), have been synthesized, their potential applications have not yet been fully investigated. However, many researchers have reported relevant results that can be a basis for the search for new potential drugs. Therefore, the aim of this study was to evaluate the cytotoxic, cytostatic, and antibacterial effects of certain 4-thiazolidinone-based derivatives, Les-3166, Les-5935, Les-6009, and Les-6166, on human fibroblasts (BJ), neuroblastoma (SH-SY5Y), epithelial lung carcinoma (A549), and colorectal adenocarcinoma (CACO-2) cell lines in vitro. All tested compounds applied in a concentration range from 10 to 100 µM were able to decrease metabolic activity in the BJ, A549, and SH-SY5Y cell lines. However, the action of Les-3166 was mainly based on the ROS-independent pathway, similarly to Les-6009. In turn, Les-5935 and Les-6166 were able to promote ROS production in BJ, A549, and SH-SY5Y cells, compared to the control. Les-3166, Les-6009, and Les-6166 significantly increased the caspase-3 activity, especially at the concentrations of 50 µM and 100 µM. However, Les-5935 did not induce apoptosis. Only Les-5935 showed a minor cytostatic effect on SH-SY5Y cells. Additionally, the antibacterial properties of the tested compounds against P. aeruginosa bacterial biofilm can be ranked as follows: Les-3166 > Les-5935 > Les-6009. Les-6166 did not show any anti-biofilm activity. In summary, the study showed that Les-5935, Les-6009, and Les-6166 were characterized by anticancer properties, especially in the human lung cancer cell. In cases of BJ, SH-SY5Y, and CACO-2 cells the anticancer usage of such compounds is limited due to effect visible only at 50 and 100 µM.

Suppression of hyphal formation and virulence of Candida albicans by natural and synthetic compounds.

Candida albicans undergoes a morphological yeast-to-hyphal transition during infection, which plays a significant role in its pathogenesis. The filamentous morphology of the hyphal form has been identified as a virulence factor as it facilitates surface adherence, intertwining with biofilm, invasion, and damage to host tissues and organs. Hence, inhibition of filamentation in addition to biofilm formation is considered a viable strategy against C. albicans infections. Furthermore, a good understanding of the signaling pathways involved in response to environmental cues driving hyphal growth is also critical to an understanding of C. albicans pathogenicity and to develop novel therapies. In this review, first the clinical significance and transcriptional control of C. albicans hyphal morphogenesis are addressed. Then, various strategies employed to suppress filamentation, prevent biofilm formation, and reduce virulence are discussed. These strategies include the inhibition of C. albicans filament formation using natural or synthetic compounds, and their combination with other agents or nanoformulations.

Identification and characterization of human interferon alpha inhibitors through a WISH cell line-based reporter gene assay.

Interferons (IFNs) are important glycoproteins which can stimulate or inhibit up to three hundred different genes encoding proteins involved in antiviral defense mechanisms, inflammation, adaptive immunity, angiogenesis and among other processes. Nevertheless, different genetic alterations may lead to interferon alpha (IFN-α) overproduction in human autoimmune diseases like systemic lupus erythematosus. As a consequence, IFN-α is a central molecule whose activity must be regulated to block their harmful effect on those disorders where the endogenous cytokine production constitutes the etiology of the illnesses. In this work, we evaluate the biological activity of eighty-eight compounds, from our own chemo-library, to find potential IFN-α inhibitors by using a reporter gene assay (RGA) WISH-Mx2/EGFP. We identified some compounds able to modulate negatively the IFN-α activity. The most active IFN-α inhibitors were further studied achieving promising results. In addition, some combinations of the most active compounds were analyzed accomplishing a stronger effect to decrease the IFN-α activity than each compound alone. Furthermore, the complete inhibition of the cytokine activity was reached with some combinations of compounds.

Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G.

Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.

Synthesis of phenoxyacyl-ethanolamides and their effects on fatty acid amide hydrolase activity.

N-Acylethanolamines (NAEs) are involved in numerous biological activities in plant and animal systems. The metabolism of these lipids by fatty acid amide hydrolase (FAAH) is a key regulatory point in NAE signaling activity. Several active site-directed inhibitors of FAAH have been identified, but few compounds have been described that enhance FAAH activity. Here we synthesized two sets of phenoxyacyl-ethanolamides from natural products, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, with structural similarity to NAEs and characterized their effects on the hydrolytic activity of FAAH. Both compounds increased the apparent Vmax of recombinant FAAH proteins from both plant (Arabidopsis) and mammalian (Rattus) sources. These NAE-like compounds appeared to act by reducing the negative feedback regulation of FAAH activity by free ethanolamine. Both compounds added to seedlings relieved, in part, the negative growth effects of exogenous NAE12:0. Cardanolethanolamide reduced neuronal viability and exacerbated oxidative stress-mediated cell death in primary cultured neurons at nanomolar concentrations. This was reversed by FAAH inhibitors or exogenous NAE substrate. Collectively, our data suggest that these phenoxyacyl-ethanolamides act to enhance the activity of FAAH and may stimulate the turnover of NAEs in vivo. Hence, these compounds might be useful pharmacological tools for manipulating FAAH-mediated regulation of NAE signaling in plants or animals.

Larvicidal Activity of Some Aromatic Thiosemicarbazone and Metal Complexes [Ni (II), Cu (II), Co (II)] Against Aedes (Stegomyia) aegypti (Linnaeus, 1762) and Aedes albopictus (Skuse, 1894) (Diptera: Culicidae) Larvae.

Objective: A series of aromatic thiosemicarbazone-oxime [TP1 and TP2] derivatives and their Ni(II), Cu(II), and Co(II) complexes were synthesized, and their larvicidal activity was evaluated against Aedes aegypti and Aedes albopictus larvae. The efficacy of these substances to Aedes albopictus larvae has been demonstrated for the first time. Methods: Laboratory colonized Aedes aegypti and Aedes albopictus larvae were subjected to larvicidal activity tests. Larval mortality rates at 24 and 48 hours were recorded and LC50 values were calculated. The study was carried out at Aydin Adnan Menderes University in 2021. Results: For Aedes aegypti, LC50 of TP1 and its Co(II) complex were 15.41, 9.75, µg/mL whereas for TP2 and its Co(II) complex, LC50 were 21.62, 20.50 µg/mL after 24 and 48 h respectively. For Aedes albopictus, TP1 and its Co(II) complex showed an LC50 of 12.06, 8.75 µg/mL, whereas TP2 and its Co(II) complex showed an LC50 of 32.87, 25.48 µg/mL, for 24, and 48 h respectively. Conclusion: Both TP1 and TP2 compounds and their Co(II) complexes presented high efficacy against the larvae; it can be said that C=S groups in thiosemicarbazone derivatives are effective in showing activity and for this reason, studies should be continued to make these components effective.

From nature to nanotechnology: The interplay of traditional medicine, green chemistry, and biogenic metallic phytonanoparticles in modern healthcare innovation and sustainability.

As we navigate the modern era, the intersection of time-honoured natural remedies and contemporary scientific approaches forms a burgeoning frontier in global healthcare. For generations, natural products have been foundational to health solutions, serving as the primary healthcare choice for 80% to 85% of the world's population. These herbal-based, nature-derived substances, significant across diverse geographies, necessitate a renewed emphasis on enhancing their quality, efficacy, and safety. In the current century, the advent of biogenic phytonanoparticles has emerged as an innovative therapeutic conduit, perfectly aligning with principles of environmental safety and scientific ingenuity. Utilizing green chemistry techniques, a spectrum of metallic nanoparticles including elements such as copper, silver, iron, zinc, and titanium oxide can be produced with attributes of non-toxicity, sustainability, and economic efficiency. Sophisticated herb-mediated processes yield an array of plant-originated nanomaterials, each demonstrating unique physical, chemical, and biological characteristics. These attributes herald new therapeutic potentials, encompassing antioxidants, anti-aging applications, and more. Modern technology further accelerates the synthesis of natural products within laboratory settings, providing an efficient alternative to conventional isolation methods. The collaboration between traditional wisdom and advanced methodologies now signals a new epoch in healthcare. Here, the augmentation of traditional medicine is realized through rigorous scientific examination. By intertwining ethical considerations, cutting-edge technology, and natural philosophy, the realms of biogenic phytonanoparticles and traditional medicine forge promising pathways for research, development, and healing. The narrative of this seamless integration marks an exciting evolution in healthcare, where the fusion of sustainability and innovation crafts a future filled with endless possibilities for human well-being. The research in the development of metallic nanoparticles is crucial for unlocking their potential in revolutionizing fields such as medicine, catalysis, and electronics, promising groundbreaking applications with enhanced efficiency and tailored functionalities in future technologies. This exploration is essential for harnessing the unique properties of metallic nanoparticles to address pressing challenges and advance innovations across diverse scientific and industrial domains.

Multitarget Compounds for Neglected Diseases: A Review.

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multi-target compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justi-fied by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multi-target potential of phenolic compounds was observed in all diseases under study, with the mecha-nisms related to the nucleus and transcription being the most reported mechanisms. From this per-spective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

From lab to nature: Recent advancements in the journey of gastroprotective agents from medicinal chemistry to phytotherapy.

Peptic ulcer, affecting 10 % of the global population, results from imbalances in gastric juice pH and diminished mucosal defences. Key underlying factors are non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori infection, undermining mucosal resistance. Traditional treatments like proton pump inhibitors (PPIs) and histamine-2 (H2) receptor antagonists exhibit drawbacks such as adverse effects, relapses, and drug interactions. This review extensively explores the ethnomedicinal, synthetic and pharmacological facets of various potential peptic ulcer treatments. Rigorous methodologies involving electronic databases, and chemical structure verification via 'PubChem' and 'SciFinder' enhance the review's credibility. The provided information, spanning medicinal insights to intricate pharmacological mechanisms, establishes a robust groundwork for future research and the development of plant-derived or synthetic molecules for peptic ulcers, offering a promising alternative to conventional therapies.

Recent Advancement in Synthesis and Bioactivities of 1,3,4-Oxadiazole.

Derivatives of 1,3,4-oxadiazole are effective in the treatment and cure of a wide range of diseases in medical chemistry, while industrial development has shown that they can be utilised as corrosion inhibitors and light-emitting diodes. The researchers discovered several promising synthetic strategies that created 1,3,4-oxadiazoles in extraordinarily high yields while using environmentally friendly methods. These compounds can potentially be used in a wide range of lifechanging applications. Stable isomeric oxadiazole forms of pleconaril, raltegravir, butalamine, fasiplon, oxolamine, and several other drugs are among the numerous potent and effective pharmaceuticals that are now on the market. Fasiplon, butalamine, raltegravir, and pleconaril treat HIV/AIDS patients. This article has attempted to bring attention to the chemistry and pharmacology of oxadiazole and its derivatives. Oxadiazole derivatives have been used extensively as prospective therapeutic agents in clinical research, and this has become standard practice. The use of biological and in-silico models has enabled scientists to identify more synthetic analogues of cancer prevention, antifungal, and anti-HIV medications. This article provides recent information regarding procedures for synthesizing 1,3,4-oxadiazoles and their biological actions on the body.

Outlining the Molecules Tested In Vivo for Chagas Disease, Malaria, and Schistosomiasis Over the Last Six Years - A Literature Review Focused on New Synthetic Drug Identities and Repurposing Strategies.

BACKGROUND: COVID-19 disrupted NTD programs in 60% of countries, impairing public health goals. Thus, boosting NTD's research knowledge is demanding, and in vivo screening of candidates allows for the prospect of promising options based on their overall profile. OBJECTIVE: In this work, we highlighted the relevant research done between 2015-2021 in the fields of synthetic and repurposed drugs that were tested in vivo for Chagas disease, malaria, and schistosomiasis. METHODS: MEDLINE, PUBMED, CAPES PERIODIC, and ELSEVIER databases were used for a comprehensive literature review of the last 6 years of research on each area/disease. RESULTS: Overall, research focused on nitro heterocyclic, aromatic nitro, nucleoside, and metal-based scaffolds for analogue-based drug generation. Repurposing was widely assessed, mainly with heterocyclic drugs, their analogues, and in combinations with current treatments. Several drug targets were aimed for Chagas treatment, specific ones such as iron superoxide dismutase, and more general ones, such as mitochondrial dysfunction. For malaria, hemozoin is still popular, and for schistosomiasis, more general structural damage and/or reproduction impairment were aimed at in vitro analysis of the mechanism of action. CONCLUSION: Latest in vivo results outlined trends for each disease - for Chagas Disease, heterocyclics as thiazoles were successfully explored; for Malaria, quinoline derivatives are still relevant, and for schistosomiasis, repurposed drugs from different classes outstood in comparison to synthetic compounds. This study uprises the continuous development of Chagas disease, malaria, and schistosomiasis drugs, providing researchers with tools and information to address such unmet therapeutic needs.