Insights on Natural Products Against Amyotrophic Lateral Sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes the death of motor neurons and consequent muscle paralysis. Despite many efforts to address it, current therapy targeting ALS remains limited, increasing the interest in complementary therapies. Over the years, several herbal preparations and medicinal plants have been studied to prevent and treat this disease, which has received remarkable attention due to their blood-brain barrier penetration properties and low toxicity. Thus, this review presents the therapeutic potential of a variety of medicinal herbs and their relationship with ALS and their physiopathological pathways.

PI3K Signaling Pathways as a Molecular Target for Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common type of cancer that affects the central nervous system (CNS). It currently accounts for about 2% of diagnosed malignant tumors worldwide, with 296,000 new cases reported per year. The first-choice treatment consists of surgical resection, radiotherapy, and adjuvant chemotherapy, which increases patients' survival by 15 months. New clinical and pre-clinical research aims to improve this prognosis by proposing the search for new drugs that effectively eliminate cancer cells, circumventing problems such as resistance to treatment. One of the promising therapeutic strategies in the treatment of GBM is the inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway, which is closely related to the process of tumor carcinogenesis. This review sought to address the main scientific studies of synthetic or natural drug prototypes that target specific therapy co-directed via the PI3K pathway, against human glioblastoma.

Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains.

BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

Naphthoquinone Derivatives Targeting Melanoma.

Cancer is responsible for high mortality rates worldwide, representing a serious health problem. In this sense, melanoma corresponds to the most aggressive type of skin cancer, being the cause of the highest death rates. Therapeutic strategies for the treatment of melanoma remain limited, with problems associated with toxicity, serious side effects, and mechanisms of resistance. The potential of natural products for the prevention and treatment of melanoma has been reported in different studies. Among these compounds, naphthoquinones (1,2-naphthoquinones and 1,4-naphthoquinones) stand out for their diverse pharmacological properties, including their antitumor activity. Thus, this review covers different studies found in the literature on the application of natural naphthoquinones targeting melanoma, providing information regarding the mechanisms of action investigated for these compounds. Finally, we believe that this review provides a comprehensive basis for the use of natural naphthoquinones against melanoma and that it may contribute to the discovery of promising compounds, specifically naphthoquinones, aimed at the treatment of this cancer.

Inhibitors Targeting Hepatitis C Virus (HCV) Entry.

Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems, such as fibrosis, steatosis, and cirrhosis, in addition to progressing to hepatocellular carcinoma and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system's activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC50 and CC50 values of 0.25 nM and >10 µM (SI: 10,000), respectively. This SRBI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC50 and CC50 values of 0.0331 and 25.1 µM, respectively), as well as in NPC1L1 (IC50 and CC50 values of 2.3 nM and > 15 µM, respectively). Thus, this review will discuss promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions, and advances in this field.

BACE-1 Inhibitors Targeting Alzheimer's Disease.

The accumulation of amyloid-ß (Aß) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of ß-secretase (ß-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aß peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aß generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.

Preclinical data on morpholine (3,5-di-tertbutyl-4-hydroxyphenyl) methanone induced anxiolysis.

Trimetozine is used to be indicated for the treatment of mental illnesses, particularly anxiety. The present study provides data on the pharmacological profile of trimetozine derivative morpholine (3,5-di-tert-butyl-4-hydroxyphenyl) methanone (LQFM289) which was designed from molecular hybridization of trimetozine lead compound and 2,6-di-tert-butyl-hydroxytoluene to develop new anxiolytic drugs. Here, we conduct molecular dynamics simulations, docking studies, receptor binding assays, and in silico ADMET profiling of LQFM289 before its behavioral and biochemical assessment in mice within the dose range of 5-20 mg/kg. The docking of LQFM289 showed strong interactions with the benzodiazepine binding sites and matched well with receptor binding data. With the ADMET profile of this trimetozine derivative that predicts a high intestinal absorption and permeability to blood-brain barrier without being inhibited by the permeability glycoprotein, the oral administration of LQFM289 10 mg/kg consistently induced anxiolytic-like behavior of the mice exposed to the open field and light-dark box apparatus without eliciting motor incoordination in the wire, rotarod, and chimney tests. A decrease in the wire and rotarod´s fall latency coupled with an increase in the chimney test´s climbing time and a decrease in the number of crossings in the open field apparatus at the dose of 20 mg/kg of this trimetozine derivative suggest sedative or motor coordination impairment at this highest dose. The attenuation of the anxiolytic-like effects of LQFM289 (10 mg/kg) by flumazenil pretreatment implicates the participation of benzodiazepine binding sites. The lowering of corticosterone and tumor necrosis factor alpha (cytokine) in LQFM289-treated mice at a single oral (acute) dose of 10 mg/kg suggests that the anxiolytic-like effect of this compound also involves the recruitment of non-benzodiazepine binding sites/GABAergic molecular machinery.

Natural Coumarin Derivatives Targeting Melanoma.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

SARS-CoV-2 Omicron Variant in Medicinal Chemistry Research.

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Nowadays, modern society has faced a new challenging problem, the emergence of novel SARS-CoV-2 variants of concern (VOCs). In this context, the Omicron (B.1.1.529) variant, having more than 60 mutations when compared to its ancestral wild-type virus, has infected many individuals around the world. It is rapidly spread person-to-person due to its increased transmissibility. Additionally, it was demonstrated that this newest variant and its subvariants have the capability of evading the host immune system, being resistant to neutralizing antibodies. Moreover, it has been proven to be resistant to monoclonal antibodies and several different vaccines. This ability is associated with a huge number of mutations associated with its spike (S) glycoprotein, which presents at least 15 mutations. These mutations are able to modify the way how this virus interacts with the host angiotensin-converting enzyme 2 (ACE2), increasing its infectivity and making the therapeutic alternatives more ineffective. Concerning its chymotrypsin-like picornavirus 3C-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp), it has been seen that some compounds can be active against different SARS-CoV-2 variants, in a similar mode than its wild-type precursor. This broad spectrum of action for some drugs could be attributed to the fact that the currently identified mutations found in 3CLpro and RNA proteins being localized near the catalytic binding site, conserving their activities. Herein this review, we provide a great and unprecedented compilation of all identified and/or repurposed compounds/drugs against this threatening variant, Omicron. The main targets for those compounds are the protein-protein interface (PPI) of S protein with ACE2, 3CLpro, RdRp, and Nucleocapsid (N) protein. Some of these studies have presented only in silico data, having a lack of experimental results to prove their findings. However, these should be considered here since other research teams can use their observations to design and investigate new potential agents. Finally, we believe that our review will contribute to several studies that are in progress worldwide, compiling several interesting aspects about VOCs associated with SARS-CoV- 2, as well as describing the results for different chemical classes of compounds that could be promising as prototypes for designing new and more effective antiviral agents.

LQM10, a guanylhydrazone derivative, reduces nociceptive and inflammatory responses in mice.

In the present study, we examined the antinociceptive and anti-inflammatory activities of a guanylhydrazone derivative, (E)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-guanylhydrazone hydrochloride (LQM10), in mice. The antinociceptive effect was determined by assessing behavioural responses in different pain models, while anti-inflammatory activity was examined in carrageenan-induced pleurisy. Intraperitoneal LQM10 administration reduced the acetic acid-induced nociceptive behaviour, a phenomenon that was unaltered by pretreatment with yohimbine, atropine, naloxone or glibenclamide. In the formalin assay, LQM10 reduced nociceptive behaviour only in the second phase, indicating an inhibitory effect on inflammatory pain. LQM10 did not alter the pain latency in the hot plate assay and did not impact the locomotor activity of mice in the rotarod assay. In the carrageenan-induced pleurisy assay, LQM10 treatment inhibited critical events involved in inflammatory responses, namely, leucocyte recruitment, plasma leakage and increased inflammatory mediators (tumour necrosis factor Like Properties of Chalchones and Flavonoid Derivatives [TNF]-α and interleukin [IL]-1ß) in the pleural exudate. Overall, these results indicate that LQM10 exhibits antinociceptive effects associated with peripheral mechanisms and anti-inflammatory activity mediated via a reduction in leucocyte migration and proinflammatory mediators, rendering this compound a promising candidate for treating pain and inflammatory process.

Nitro compounds against trypanosomatidae parasites: Heroes or villains?

Chagas disease and Human African trypanosomiasis (HAT) are caused by Trypanosoma cruzi, T. brucei rhodesiense or T. b. gambiense parasites, respectively; while Leishmania is caused by parasites from the Leishmania genus. In recent years, many efforts have been addressed to develop inhibitors against these parasites, especially nitro-containing derivatives, which can interfere with essential enzymes from the protozoa. In this review, all anti-trypanosomatidae nitrocompounds reported so far are shown herein, highlighting their activities and SAR analyses, providing all the benefits and problems associated with this ambiguous chemical group. Finally, this review paper will be useful for many research teams around the world, which are searching for novel trypanocidal and leishmanicidal agents.

Hybrid-Compounds Against Trypanosomiases.

Neglected tropical diseases (NTDs) are a global public health problem associated with approximately 20 conditions. Among these, Chagas disease (CD), caused by Trypanosoma cruzi, and human African trypanosomiasis (HAT), caused by T. brucei gambiense or T. brucei rhodesiense, affect mainly the populations of the countries from the American continent and sub- Saharan Africa. Pharmacological therapies used for such illnesses are not yet fully effective. In this context, the search for new therapeutic alternatives against these diseases becomes necessary. A drug design tool, recently recognized for its effectiveness in obtaining ligands capable of modulating multiple targets for complex diseases, concerns molecular hybridization. Therefore, this review aims to demonstrate the importance of applying molecular hybridization in facing the challenges of developing prototypes as candidates for the treatment of parasitic diseases. Therefore, studies involving different chemical classes that investigated and used hybrid compounds in recent years were compiled in this work, such as thiazolidinones, naphthoquinones, quinolines, and others. Finally, this review covers several applications of the exploration of molecular hybridization as a potent strategy in the development of molecules potentially active against trypanosomiases, in order to provide information that can help in designing new drugs with trypanocidal activity.

Strategies in Medicinal Chemistry to Discover New Hit Compounds against Ebola Virus: Challenges and Perspectives in Drug Discovery.

Ebola Virus (EBOV) is an infectious disease that mainly affects the cardiovascular system. It belongs to the Filoviridae family, consisting of filamentous envelopes and non-segmented negative RNA genome. EBOV was initially identified in Sudan and Zaire (now named the Democratic Republic of Congo) around 1967. It is transmitted mainly by contact with secretions (blood, sweat, saliva, and tears) from infected wild animals, such as non-human primates and bats. It has gained more prominence in recent years due to the recent EBOV outbreaks that occurred from 2013 to 2016, resulting in approximately 28,000 infected individuals, with a mortality rate of 40- 70%, affecting mainly Liberia, Guinea, and Sierra Leone. Despite these alarming levels, there is still no FDA-approved drug for the effective treatment of these diseases. The most advanced drug to treat EBOV is remdesivir. However, it is a high-cost drug and is available only for intravenous use. In this sense, more investments are needed in the research focused on the development of new antiviral drugs. In this context, medicinal chemistry strategies have been improving and increasingly discovering new hits that can be used in the future as a treatment against these diseases. Thus, this review will address the main advances in medicinal chemistry, such as drug discovery through computational techniques (virtual screening and virtual high throughput screening), drug repurposing, phenotypic screening assays, and employing classical medicinal chemistry, such as bioisosterism, metabolism-based drug design, and the discovery of new inhibitors through natural products, thereby presenting several promising compounds that may contain the advance of these pathogens.

Medicinal Chemistry of Inhibitors Targeting Resistant Bacteria.

The discovery of antibiotics was a revolutionary feat that provided countless health benefits. The identification of penicillin by Alexander Fleming initiated the era of antibiotics, represented by constant discoveries that enabled effective treatments for the different classes of diseases caused by bacteria. However, the indiscriminate use of these drugs allowed the emergence of resistance mechanisms of these microorganisms against the available drugs. In addition, the constant discoveries in the 20th century generated a shortage of new molecules, worrying health agencies and professionals about the appearance of multidrug-resistant strains against available drugs. In this context, the advances of recent years in molecular biology and microbiology have allowed new perspectives in drug design and development, using the findings related to the mechanisms of bacterial resistance to generate new drugs that are not affected by such mechanisms and supply new molecules to be used to treat resistant bacterial infections. Besides, a promising strategy against bacterial resistance is the combination of drugs through adjuvants, providing new expectations in designing new antibiotics and new antimicrobial therapies. Thus, this manuscript will address the main mechanisms of bacterial resistance under the understanding of medicinal chemistry, showing the main active compounds against efflux mechanisms, and also the application of the use of drug delivery systems, and finally, the main potential natural products as adjuvants or with promising activity against resistant strains.

Computer-Aided Drug Design of Anti-inflammatory Agents Targeting Microsomal Prostaglandin E2 Synthase-1 (mPGES-1).

Inflammation is a natural reaction to external stimuli to protect the organism. However, if it is exaggerated, it can cause severe physiopathological damage, linked to diseases like rheumatoid arthritis, cancer, diabetes, allergies, and infections. Inflammation is mainly characterized by pain, increased temperature, flushing, and edema, which can be controlled using anti-inflammatory drugs. In this context, prostaglandin E2 (PGE2) inhibition has been targeted for designing new compounds with anti-inflammatory properties. It is a bioactive lipid overproduced during an inflammatory process, in which its increased production is carried out mainly by COX-1, COX-2, and microsomal prostaglandin E2 synthase-1 (mPGES-1). Recently, studies have demonstrated that mPGES-1 inhibition is a safe strategy for developing anti-inflammatory agents, which could protect against pain, acute inflammation, arthritis, autoimmune diseases, and different types of cancers. Thus, in recent years, computer-aided drug design (CADD) approaches have been increasingly used to design new inhibitors, decreasing costs and increasing the probability of discovering active substances. Finally, this review will cover all aspects involving high-throughput virtual screening, molecular docking, dynamics, fragment-based drug design, and quantitative structure-activity relationship in seeking new promising mPGES-1 inhibitors.

Multi-target Approaches of Epigallocatechin-3-O-gallate (EGCG) and its Derivatives against Influenza Viruses.

Influenza viruses (INFV), the Orthomyxoviridae family, are mainly transmitted among humans via aerosols or droplets from the respiratory secretions. However, fomites could be a potential transmission pathway. Annually, seasonal INFV infections account for 290-650 thousand deaths worldwide. Currently, there are two classes of approved drugs to treat INFV infections, being neuraminidase (NA) inhibitors and blockers of matrix-2 (M2) ion channel. However, cases of resistance have been observed for both chemical classes, reducing the efficacy of treatment. The emergence of influenza outbreaks and pandemics calls for new antiviral molecules that are more effective, and that could overcome the current resistance to anti-influenza drugs. In this context, polyphenolic compounds are found in various plants, and these have displayed different multi-target approaches against diverse pathogens. Among these, green tea (Camellia sinensis) catechins, in special epigallocatechin-3-O-gallate (EGCG), have demonstrated significant activities against the two most relevant human INFV, subtypes A and lineages B. In this sense, EGCG has been found to be a promising multi-target agent against INFV since it can act inhibiting NA, hemagglutination (HA), RNA-dependent RNA polymerase (RdRp), and viral entry/adsorption. In general, the lack of knowledge about potential multi-target natural products prevents an adequate exploration of them, increasing the time for developing multi-target drugs. Then, this review aimed to compile most relevant studies showing the anti-INFV effects of EGCG and its derivatives, which could become antiviral drug prototypes in the future.

Bradykinin-target therapies in SARS-CoV-2 infection: current evidence and perspectives.

Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that preferentially infects the respiratory tract. Bradykinin (BK) is a hypotensive substance that recently emerged as one of the mechanisms to explain COVID-19-related complications. Concerning this, in this review, we try to address the complex link between BK and pathophysiology of COVID-19, investigating the role of this peptide as a potential target for pharmacological modulation in the management of SARS-CoV-2. The pathology of COVID-19 may be more a result of the BK storm than the cytokine storm, and which BK imbalance is a relevant factor in the respiratory disorders caused by SARS-CoV-2 infection. Regarding this, an interesting point of intervention for this disease is to modulate BK signaling. Some drugs, such as icatibant, ecallantide, and noscapine, and even a human monoclonal antibody, lanadelumab, have been studied for their potential utility in COVID-19 by modulating BK signaling. The interaction of the BK pathway and the involvement of cytokines such as IL-6 and IL1 may be key to the use of blockers, even if only as adjuvants. In fact, reduction of BK, mainly DABK, is considered a relevant strategy to improve clinical conditions of COVID-19 patients. In this context, despite the current unproven clinical efficacy, drugs repurposing that block B1 or B2 receptor activation have gained prominence for the treatment of COVID-19 in the world.

TNF-α Inhibitors from Natural Compounds: An Overview, CADD Approaches, and their Exploration for Anti-inflammatory Agents.

Inflammation is a natural process that occurs in the organism in response to harmful external agents. Despite being considered beneficial, exaggerated cases can cause severe problems for the body. The main inflammatory manifestations are pain, increased temperature, edema, decreased mobility, and quality of life for affected individuals. Diseases such as arthritis, cancer, allergies, infections, arteriosclerosis, neurodegenerative diseases, and metabolic problems are mainly characterized by an exaggerated inflammatory response. Inflammation is related to two categories of substances: pro- and anti-inflammatory mediators. Among the pro-inflammatory mediators is Tumor Necrosis Factor-α (TNF-α). It is associated with immune diseases, cancer, and psychiatric disorders which increase its excretion. Thus, it becomes a target widely used in discovering new antiinflammatory drugs. In this context, secondary metabolites biosynthesized by plants have been used for thousands of years and continue to be one of the primary sources of new drug scaffolds against inflammatory diseases. To decrease costs related to the drug discovery process, Computer-Aided Drug Design (CADD) techniques are broadly explored to increase the chances of success. In this review, the main natural compounds derived from alkaloids, flavonoids, terpene, and polyphenols as promising TNF-α inhibitors will be discussed. Finally, we applied a molecular modeling protocol involving all compounds described here, suggesting that their interactions with Tyr59, Tyr119, Tyr151, Leu57, and Gly121 residues are essential for the activity. Such findings can be useful for research groups worldwide to design new anti-inflammatory TNF-α inhibitors.

Molecular Modeling Targeting Transmembrane Serine Protease 2 (TMPRSS2) as an Alternative Drug Target Against Coronaviruses.

Since December 2019, the new Coronavirus disease (COVID-19) caused by the etiological agent SARS-CoV-2 has been responsible for several cases worldwide, becoming pandemic in March 2020. Pharmaceutical companies and academics have joined their efforts to discover new therapies to control the disease since there are no specific drugs to combat this emerging virus. Thus, several tar-gets have been explored; among them, the transmembrane protease serine 2 (TMPRSS2) has gained greater interest in the scientific community. In this context, this review will describe the importance of TMPRSS2 protease and the significant advances in virtual screening focused on discovering new inhibitors. In this review, it was observed that molecular modeling methods could be powerful tools in identifying new molecules against SARS-CoV-2. Thus, this review could be used to guide re-searchers worldwide to explore the biological and clinical potential of compounds that could be promising drug candidates against SARS-CoV-2, acting by inhibition of TMPRSS2 protein.

Synthesis, Antileishmanial Activity and in silico Studies of Aminoguanidine Hydrazones (AGH) and Thiosemicarbazones (TSC) Against Leishmania chagasi Amastigotes.

BACKGROUND: Leishmaniasis is a worldwide health problem, highly endemic in developing countries. Among the four main clinical forms of the disease, visceral leishmaniasis is the most severe, fatal in 95% of cases. The undesired side-effects from first-line chemotherapy and the reported drug resistance search for effective drugs that can replace or supplement those currently used in an urgent need. Aminoguanidine hydrazones (AGH's) have been explored for exhibiting a diverse spectrum of biological activities, in particular the antileishmanial activity of MGBG. The bioisosteres thiosemicarbazones (TSC's) offer a similar biological activity diversity, including antiprotozoal effects against Leishmania species and Trypanosoma cruzi. OBJECTIVES: Considering the impact of leishmaniasis worldwide, this work aimed to design, synthesize, and perform a screening upon L. chagasi amastigotes and for the cytotoxicity of the small "inhouse" library of both AGH and TSC derivatives and their structurally-related compounds. METHODS: A set of AGH's (3-7), TSC's (9, 10), and semicarbazones (11) were initially synthesized. Subsequently, different semi-constrained analogs were designed and also prepared, including thiazolidines (12), dihydrothiazines (13), imidazolines (15), pyrimidines (16, 18) azines (19, 20), and benzotriazepinones (23-25). All intermediates and target compounds were obtained with satisfactory yields and exhibited spectral data consistent with their structures. All final compounds were evaluated against L. chagasi amastigotes and J774.A1 cell line. Molecular docking was performed towards trypanothione reductase using GOLD® software. RESULTS: The AGH's 3i, 4a, and 5d, and the TSC's 9i, 9k, and 9o were selected as valuable hits. These compounds presented antileishmanial activity compared with pentamidine, showing IC50 values ranged from 0.6 to 7.27 µM, maximal effects up to 55.3%, and satisfactory SI values (ranged from 11 to 87). On the other hand, most of the resulting semi-constrained analogs were found cytotoxic or presented reduced antileishmanial activity. In general, TSC class is more promising than its isosteric AGH analogs, and the beneficial aromatic substituent effects are not similar in both series. In silico studies have suggested that these hits are capable of inhibiting the trypanothione reductase from the amastigote forms. CONCLUSION: The promising antileishmanial activity of three AGH's and three TSC's was characterized. These compounds presented antileishmanial activity compared with PTD, showing IC50 values ranged from 0.6 to 7.27 µM, and satisfactory SI values. Further pharmacological assays involving other Leishmania strains are in progress, which will help choose the best hits for in vivo experiments.