Resumo em Inglês:

Leishmaniasis is an infectious disease caused by protozoan parasites of the Leishmania genus and affects more than 90 countries, especially in tropical and subtropical regions. The first treatment for these diseases involves pentavalent antimonial derivatives, which are very toxic and cause severe side effects. The other chemotherapeutic drugs used as second-line agents include different organic compound classes, such as pentamidine, which also cause severe side effects. Thus, new, safer, and efficient antileishmaniasis agents are urgently needed to control and treat these diseases. This mini review, which considered the last two decades of related research, highlighted the principal synthetic methodologies used to access amidine derivatives, focusing on more eco-friendly methods. Furthermore, the results obtained from evaluations of the anti-Leishmania activity and several molecular targets of the amidine derivatives are highlighted.

Resumo em Inglês:

Nitroaromatic drugs represent an important class of therapeutic agents, endowed with different pharmacological properties such as antibacterial, antiprotozoal, anti-Parkinson, anticancer, etc. However, the nitroheterocycle and nitroarene fragments are considered potentially toxic, with reports of mutagenicity and genotoxicity. The bioreduction process of the nitro group plays a central role in the antimicrobial and toxicological mechanism of action of nitroaromatic drugs. This article will review the nitroaromatic drugs approved by the Food and Drug Administration (FDA) in the last 30 years, the mechanisms of bioactivation, metabolism and toxicity and, finally, it will revisit the main methodologies for obtaining the nitroaromatic fragment from aromatic nitration reaction and oxidation of arylamines and/or heteroarylamines.

Resumo em Inglês:

In this review, the works carried out in Brazil with multicomponent reactions over a period of 30 years were mapped through search in the literature (PubMed, Scopus, and Web of Science). A significant increase in papers with multicomponent reactions in Brazil was identified. In total, 243 articles with 6,672 citations (average of 27.46 citations per article) were found. Biginelli, Ugi, Mannich, Passerini and Hantzsch are the most employed reactions, and the articles were classified in medicinal chemistry, catalyst, mechanism, green chemistry, asymmetric synthesis and fluorescent. A bibliometric analysis with the 243 articles was performed, including the number of publications, citations, predominant journals, Brazilian universities with the highest number of publications on the subject, and international collaborations.

Resumo em Inglês:

Natural products have long been explored in the history of most cultures worldwide. They have been mainly applied in the therapy of some diseases and for food preservation due to the antimicrobial properties of some condiments. Most of this knowledge was empirically discovered and passed from generation to generation. Over the last few years, the evolution of organic chemistry and the techniques of analysis and purification of compounds from complex matrices enabled a significant increase in research to identify bioactive products isolated from plants. In this paper, we briefly discuss the relevance of natural products on drug development, mainly focusing on amide piperine, the main chemical constituent of black pepper (Piper nigrum). Its antiparasitic activities and the knowledge of possible mechanisms of action against different parasites provide essential information for drug development. Furthermore, its compatibility with medicinal and synthetic chemistry techniques allows the development of more effective drug candidates.

Resumo em Inglês:

The concept of privileged structures in medicinal chemistry refers to commonly found substructures in approved drugs and lead small molecules, presenting a broad profile of pharmacological action, i.e., participating in the recognition by several classes of pharmacological targets or by modulating physicochemical properties. Privileged structures are also related to nontoxic effects, which make their use in the design of new drug candidates very attractive. In contrast, another concept also refers to structures or substructures capable of presenting a pleiotropic profile for several pharmacological targets, referred to as promiscuous compounds. Worth mentioning, more recently, a great majority of promiscuous compounds have been classified as Pan Assay Interference Compounds (PAINS). In its great majority, PAINS are electrophilic in nature, capable of covalently reacting indiscriminately with several pharmacological targets, and are associated with specific substructures, which are, in turn, used as an exclusion filter during screening campaigns. This work aims to critically discuss the thin line that separates the two concepts, clarifying their differences from a molecular and pharmacological point of view. Moreover, special considerations regarding PAINS and exclusion filters will be made.

Resumo em Inglês:

The amino-quinazoline scaffold stands out as a privileged structure in Medicinal Chemistry, due to its pleiotropic pharmacological profile. It has been explored in the design and development of novel drug candidates for several therapeutic applications, including antihypertensive, anti-inflammatory, antipsychotic, anti-Alzheimer, anticancer, antiviral, antibiotic, and antiparasitic treatments, among others. The therapeutic value of amino-quinazoline drugs was first demonstrated with the use of alpha 1-adrenoceptor antagonists, such as prazosin, doxazosin and terazosin. These drugs were initially approved for the treatment of hypertension and later for the treatment of benign prostatic hyperplasia. Several amino-quinazoline kinase inhibitors were introduced into the clinic as innovative therapeutic alternatives for cancer treatment after the U.S. Food and Drug Administration approved gefitinib in 2003 as a novel epidermal growth factor receptor inhibitor drug for non-small cell lung cancer. More recently, in 2021, the kinase inhibitor belumosudil was launched as a third-line therapy for adult and pediatric patients with chronic graft-versus-host disease. This article reviews the synthetic preparation methods and pharmacological activities of bioactive amino-quinazolines described in recent decades.

Resumo em Inglês:

The proteome of Plasmodium falciparum (Pf) is abundant in intrinsically disordered proteins (IDPs). Their important roles in the malaria life cycle and the limitations of experimental and computational methods to study this class of proteins hinder the development of antimalarial drugs. At the same time, the growing interest in IDPs and theoretical tools suggest a path for their classification and functional understanding: searching databases with experimental notes and predictions of protein disorder, developing force fields to describe protein flexibility, and using molecular dynamics enhanced sampling techniques to properly sample the IDP conformational diversity. This review discusses possibilities of exploration of Pf’s IDPs and their availability in disordered-protein databases to foster molecular modeling studies. The large percentage of intrinsic disorder present in many antigens and their ability to interact with different targets, make these proteins a major class of interest in the area of drug and vaccine development.

Resumo em Inglês:

Molecular modeling soon attracted the attention of Medicinal Chemistry researchers, given the importance of molecular structure for understanding the mode of action and for designing bioactive compounds. Computer-assisted drug design (CADD) has become widespread and today big pharmaceutical companies routinely uses it as a support tool in the search for new drugs. Here, it will be addressed the most relevant topics about CADD from the last 30 years, when research groups in Medicinal Chemistry began to explore molecular modeling in Brazil. This history can be described through phases in which some methods emerged and became predominant, in a continuous evolution, passing, for example, from the basic empirical field and quantum mechanics molecular modeling procedures, through quantitative structure-activity relationship (QSAR) methods, molecular docking and, more recently, virtual screening. Since the mid-2000s, machine learning methods have been increasingly applied to the solution of problems in the context of Medicinal Chemistry, such as the determination of protein 3D structure and the characterization of relationships between chemical structures and their biological activities. Far from being complete, this history continues its evolution, bringing significant contributions to the drug design, either by reducing the time and cost of research, or by enabling and accelerating the finding for new bioactive compounds.

Resumo em Inglês:

Neglected tropical diseases (NTDs) encompass a diverse group of 20 medical conditions triggered by various pathogens, including viruses, bacteria, protozoa, and parasitic worms. Diseases caused by parasitic protozoa and parasitic worms show the highest incidence worldwide. NTDs predominantly afflict impoverished communities in tropical regions, although some exhibit a broader geographic reach. It is estimated that over 1 billion people suffer from NTDs, spanning 149 countries. Additionally, malaria is caused by protozoa of the genus Plasmodium and is highly prevalent in similar geographic regions. New drugs are urgently needed for the treatment of these diseases. In the last decades, various research groups have endeavored to develop organometallic compounds with potential applications as drugs against malaria and NTDs diseases caused by trypanosomatid parasites and parasitic helminths. This perspective highlights selected efforts from these groups in the pursuit of innovative therapeutic solutions. Relevant bioorganometallic compounds belonging to the typical classes of metallocenes, “half sandwich” M-arenes and metal carbonyls will be particularly described.

Resumo em Inglês:

Structure-based virtual screening (SBVS) is an important approach that makes the first stages of drug development and repurposing processes faster and more efficient. Advances in experimental techniques and in silico computational modeling have contributed significantly to the characterization of diverse biological targets. Combined with the rapidly growing number of chemical compounds available in virtual databases, these advances enable the effective application of SBVS for prioritization of putative bioactive compounds to treat a wide range of pathologies. Techniques such as molecular docking, along with the utilization of pharmacophore models, are commonly employed for screening large databases of compounds, providing a solid foundation for employing SBVS in drug development pipelines. This review comprehensively analyzes recent advancements and strategies employed in the field of SBVS and explores methodologies for validation, limitations, and challenges associated with this approach. Through a series of case studies across different therapeutic targets, we demonstrate SBVS’s versatility and efficacy in identifying potential therapeutic agents. However, challenges remain, and understanding these is crucial for maximizing SBVS’s potential. We address these challenges, offering insights into the current limitations and future prospects of SBVS in drug development.

Resumo em Inglês:

Cruzipain is the principal protease of Trypanosoma cruzi, the etiological agent of Chagas disease. Since its discovery in the 1980s and the resolution of the crystal structure of cruzain (a truncated recombinant form of the enzyme) in 1995, this target has attracted the interest of many research groups for screening studies, structure-based and ligand-based drug design campaigns, which include peptide-like and non-peptide synthetic compounds. In this context, empirical and computational methods have proven to be valuable tools for the study of mechanisms of action, potential binding modes and structure-activity relationships for a diverse series of cruzain/cruzipain inhibitors. This paper, therefore, reviews some of the most relevant chemical groups reported as cruzain inhibitors over the last 30 years of research.

Resumo em Inglês:

During the past 30 years, molecular simulations (MS) have become increasingly popular among medicinal chemists, being recognized as a promising tool to reduce drug development costs and timelines while increasing its success. From the refinement of docking experiments during the 1990’s to the contemporary possibility to produce accurate models of ligand intrinsic activity and affinity, the use of simulations in medicinal chemistry has progressed rapidly, becoming an essential tool in modern drug discovery pipelines. However, in spite of their potential, in silico methods and MS have historically been dependent on a tradeoff between computational cost and accuracy, which not uncommonly limits their impacts on drug development. In this context, this review presents a concise and up-to-date summary of the role of MS in medicinal chemistry, and examines its participation in recent advancements of both ligand-based and structure-based drug discovery, free-energy predictions, and model accuracies. In addition to offering a synopsis of the potential benefits of MS on drug discovery, this review intends to aid users to both understand the limitations of computational methods and to design more accurate experiments that, as a consequence, will have an increasing impact on the development of new therapeutics.

Resumo em Inglês:

Cannabis plant has been known for its medicinal use for centuries. Recent research into its pharmacology has revealed medicinal properties, promoting the use of cannabis for therapeutic purposes and consequently the growth in the production of medicinal cannabis-based products. The potency of cannabinoids in products for therapeutic purposes is essential to assess their effects on health. Medicinal cannabis products, based on extracts from the cannabis plant, however, lack standardization in both preparation and quality control. In this review, chromatographic methods and alternative strategies are described for qualitative and quantitative analysis of cannabinoids in cannabis-based products. The direct application of portable spectroscopic techniques on cannabis farms for monitoring plant growth is also reported. Finally, a special section has been dedicated to the use of chemometric tools that have been employed in the field of cannabis including methods utilizing chemometric tools such as exploratory analysis, multivariate classification, and calibration.

Resumo em Inglês:

The past 30 years have been transformative in the landscape of drug discovery, and certainly one of the most ground-breaking areas was kinase research. Since its start in the mid-1990s, kinase studies have reached notable hallmarks, ranging from the development of the first inhibitor, to innovative treatment options for a range of diseases. Today, kinases remain a pivotal protein class in drug discovery. Contemporarily, the Brazilian medicinal chemistry scene has also evolved, and followed up to such trends in the global landscape of research. Notably, the creation of the Summer School of Pharmaceutical and Medicinal Chemistry (EVQFM, in portuguese) in 1995, and its subsequent 30 consecutive editions, has raised the interest and knowledge of multiple generations in Brazil. This review aims to briefly outline the history of kinase inhibitor research, some of its landmarks, and highlight some of the contributions of Brazilian researchers to this important field of medicinal chemistry.

Resumo em Inglês:

Since Locher proposed the concept of boron neutron capture therapy (BNCT) in 1936, it has become a great challenge in the field of medicinal chemistry. The great dare has been to obtain boron-containing compounds that selectively accumulate in the organ to be irradiated. Polyhedral boron clusters (PBC) have been considered attractive moieties for the development of BNCT-agents due to their large contribution of boron per molecule. Various issues arose in the first efforts to develop PBC during the 1940-1950s that prevented their application in BNCT clinical trials, such as a lack of selectivity and low boron tumor-accumulation. Currently, the most studied PBC in BNCT are the icosahedral dicarba-closo-dodecaboranes (C2B10H12) commonly referred to carboranes and, to a lesser extent, their mono-anionic derivatives resulting from the loss of a B-vertex, commonly known as nido-carborane, and their metal complexes, known as metallacarboranes. This review will cover the medicinal chemistry of PBC for BNCT.

Resumo em Inglês:

Cannabidiol is a metabolite present in Cannabis with several pharmacological properties, including neuroprotection, anti-convulsive, antimicrobial, antinociceptive, and anti-inflammatory. Although these activities are promising for drug development and clinical uses, the neuroprotective action is the most investigated, while the anti-inflammatory and antinociceptive mechanisms are not fully known. Therefore, this brief review aims to report the knowledge advances over the last 3 decades regarding the anti-inflammatory and anti-nociceptive/analgesic properties of cannabidiol and its derivatives or analogues designed as novel drug candidates. Recent studies of the mechanisms of action underlying the anti-inflammatory effects of cannabidiol have revealed its interaction with different inflammatory mediators, including cannabinoid receptor 1 and cyclooxygenase 2, among others. On the other hand, there is a lack of information related to the analgesic activity of cannabidiol, with some reports pointing out the involvement only of transient receptor potential vanilloid receptors. In addition, several cannabidiol derivatives and structural analogues with anti-inflammatory and antinociceptive activities have been described, but their mechanisms of action have not yet been fully elucidated. Therefore, it is clear that greater efforts are still needed to unravel the mechanisms involved in such activities of great interest in drug discovery.

Resumo em Inglês:

Drug repositioning involves the use of a determined drug in a different indication and has been widely used for some therapeutic classes. Artificial intelligence, in turn, has been a trend in the modern world of innovation, including in drug design. Those approaches are apparently paradoxical (the former is not considered as properly an innovative method to introduce new molecules/drugs into the market, although the latter is) can be used as complementary. In this review, we present some concepts of both methods, their advantages, possible disadvantages, and some applications in drug design in general to improve different aspects of drug development. Examples of the use of both methods together have been given for many therapeutic classes. Notwithstanding, their application in the search for drugs for neglected diseases, although somehow stimulated, deserves more discussion, mainly in light of the social aspects of these infections.

Resumo em Inglês:

Currently, most drugs have their mode of action based on occupation-oriented pharmacology (proteins modulation through temporary inhibition by association and dissociation). Alternative modes of actions are welcome to exploit current known targets (in a more selective way, for example) as well as those known as “undruggable”. PROTAC (protheolysis targeting chimera) technology provides a compelling new approach that is based on an event-driven mode of action, exploring simultaneous binding to a protein and an E3 ligase, leading to targeted protein degradation, modulating the proteins levels. After all progress over the past two decades and the recent level of interest, clearly targeted protein degradation mode of action could become a therapeutic modality in the future. Furthermore, several PROTACs are under clinical trials, even already progressing to phase 3 (i.e., ARV-471). In this review we addressed the PROTACs discovery process, mode of action, evolution, current stage, their design, applications to modulating inflammatory conditions and the future directions of this promising drug discovery modality, including problems that still need to be overcome.

Resumo em Inglês:

Hotspots situated at protein-protein interfaces, allosteric and orthosteric binding sites, traditionally play a crucial role in the initial phases of drug discovery, as they are useful to identify druggable targets and guide the optimization of fragments into lead compounds. Despite the high level of protein frustration, which can be thought of as the percentage of residues that cannot independently achieve minimum energy due to tridimensional restraints, observed at those locations, limited efforts have been made to investigate any potential connection between the localized frustration and hotspots in proteins. This review paper aims to partially address this knowledge gap by proposing that the origin of hotspots is, at least in part, due to localized frustration in proteins. While there is no hard evidence to support this hypothesis, the results obtained by integrating in silico tools predicting hot spot locations, with those calculating localized protein frustration, suggest that druggable hotspots are surrounded by residues involved in frustrated contacts. Additionally, the inclusion of long-range electrostatic terms in the protein frustration calculation enables the identification of an equal to a higher number of frustrated residues. These observations indirectly suggest that localized protein frustration around druggable hotspots could guide the development of more potent leads.

Resumo em Inglês:

Modified flavonoids of the sub-group of pterocarpans, 5-carba-pterocarpans, 5-carbapterocarpens, 1-carba-isoflavanones, coumestans, and aurones were synthesized and evaluated as antiproliferative, antileishmanial and antiviral. A new scaffold, called pterocarpanquinone, was discovered and LQB-118, the prototypical scaffold of its series, showed consistent antileishmanial (mice and hamster in vivo) and antineoplastic (respectively, human and mice tumors ex vivo and in vivo) activity. 5-Carpa-pterocarpan LQB-485 is potent towards SF-295 cancer cells (CNS). LQB-262 and LQB-34 are new inhibitors of NB5S RdRp polymerase of hepatitis C virus (HCV) while LQB-314 and LQB-360 demonstrated potent activity and selectivity against HCV replicon reporter cells. LQB-454 and LQB-501 were evaluated for their in vitro anti-proliferative effects against human breast cancer and leukemia cell lines with diverse profiles of drug resistance. In breast cancer they present higher toxicity on multidrug resistant cells (collateral sensitivity). Aurone LQB-814, featuring a “lipophilic phenol” at A-ring”, was a very potent and selective inhibitor of SARS-CoV-2 in Calu-3 cells. Other four aurones bearing EC50 (concentration required to inhibit 50% of cell growth) < 1 were also discovered.

Resumo em Inglês:

This account describes the analysis of the Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio) chemical library as a valuable resource for early drug discovery studies. LASSBio has been using medicinal chemistry strategies for almost 30 years to design new prototype compounds with a focus on pharmacological activity. The LASSBio Chemical Library (LCL) is a collection of more than 2000 compounds, and the aim of this work was to characterize its chemical diversity and to perform a molecular repositioning study to identify ligands of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), a validated target for leukemia treatment. To achieve this, cheminformatic tools were utilized to analyze the chemical diversity of the LCL. The analysis allowed the identification of the most representative compounds of this collection, showing that the N-acylhydrazone chemotype is present in approximately 50% of the compounds. Furthermore, the compounds in this chemical library demonstrated remarkable compliance with both the Lipinski’s (93% of the compounds) and Veber’s (96% of the compounds) rules. In the study on molecular repositioning, 10 compounds were selected through virtual screening to test their enzymatic inhibition of FLT3 kinase. Among them, 4-((6,7-dimethoxyquinazolin-4-yl)amino) benzamide (LASSBio-2166) (31) showed a half-maximal inhibitory concentration (IC50) = 194 nM. Optimization of the identified hit and further studies to compare the diversity of the LCL with other libraries are perspectives of this work.

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The interactive profile between four 1,4-naphthoquinone derivatives (1-4) and human serum albumin (HSA) was studied by spectroscopic techniques and in silico calculations. The bimolecular quenching rate constant (kq ca. 1012 L mol-1 s-1) and the time-resolved fluorescence decays indicated a static fluorescence quenching mechanism. Thus, there is a spontaneous ground-state association, and based on both Stern-Volmer, modified Stern-Volmer, and van’t Hoff approaches, the association is moderate mainly driven by hydrophobic forces. The circular dichroism (CD) analysis indicated that until the proportion albumin:compound of 1:8 there is a weak perturbation on the structural content of albumin, while molecular docking results suggested subdomain IIA (site I), a positive electrostatic pocket, as the main binding site. Overall, even though the hydrogen atom replacement by methyl, fluorine, or chlorine atoms in the para position of the aromatic ring in the benzo[g]chromene-5,10-dione moiety changes the lipophilicity, it does not change the binding profile to HSA.

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The triruthenium ortho-metallated phenazine [Ru3O(CH3COO)5(py)2(dppzCl)]PF6 (1, py = pyridine; dppz-Cl = 7-chlorodipyrido[3,2-a:2’,3’-c]phenazine) is a potential metallo-drug candidate with in vitro anticancer and trypanosomicidal activities. It also showed strong interactions with deoxyribonucleic acid (DNA) and human serum albumin due to the presence of the planar and π-conjugated phenazine in its structure. Pursuing our interest in compound 1 behavior in a biological environment, we described its interaction with the cytochrome P450 (CYP450) enzymes present in human liver microsomes through a preliminary in vitro metabolism assay. This study showed that the human liver microsomes metabolized compound 1 in a concentration dependent manner. A phenotyping study suggests that CYP3A is the primary enzyme involved in the interaction, even though other isoforms metabolized 1 in a minor extent. It is worth mentioning that the results of phenotyping using supersomes should be interpreted cautiously, taking into account the inhibitory effect of the surfactant employed. Blind molecular docking results agreed with the experimental trend, showing the highest interactive profile with the isoforms CYP3A4 and 3A5, and suggested hydrophobic, π-stacking, and hydrogen bonds as the primary intermolecular forces responsible for the protein-compound interaction.