Heberth de Paula

A growing global population and increasingly stringent food-security demands, together with evolving challenges such as crop diseases, resistant weeds, and agrochemical-resistant pathogenic microorganisms, require new strategies to safeguard agricultural productivity. Succinate dehydrogenase (SDH, also known as complex II) participates in both the tricarboxylic acid cycle and the mitochondrial respiratory chain in pathogenic fungi, thereby affecting fungal metabolism and mitochondrial respiration. This enzyme has therefore been widely explored as a target in the search for new fungicides. Currently, 25 commercially available succinate dehydrogenase inhibitors (SDHIs) are used to protect economically important crops. The discovery of new agrochemicals is driven by the need to mitigate annual losses in agricultural productivity, estimated at approximately US$220 billion per year. This review summarizes advances in the synthesis of potent SDHIs over the last decade, including semisynthetic approaches and strategies combining carboxamide scaffolds with heterocyclic moieties based on bioisosterism, scaffold hopping, and molecular hybridization. The studies summarized here show that numerous hit compounds have recently been synthesized with EC50 values against several fungal strains and IC50 values for SDH inhibition that compare favorably with those of reference agrochemicals such as boscalid, thifluzamide, fluxapyroxad, fenfuram, and fluopyram. Finally, both established and emerging synthetic methods aimed at accelerating the generation of large compound libraries are increasingly supported by robust computational approaches, including 3D-QSAR and molecular dynamics simulations, to predict binding modes and provide structural insights for future investigations.

Acetylcholinesterase (AChE) is an important molecular target in the development of insecticides, but due to also being found in the human body, it is necessary to characterize the inhibitory profile of compounds to achieve selectivity. In this study, we employed molecular modeling and 3D-QSAR approaches to identify novel compounds that inhibit AChE1 in Bemisia tabaci, a common agricultural pest in tropical and subtropical crops. We conducted molecular docking simulations and quantitative structure–activity relationship analysis (QSAR) to identify compounds with potential inhibitory activity and to develop a predictive model for the activity of these new compounds. The validated model demonstrated remarkable predictive performance. Using the model, we screened a library of novel moieties in favorable regions of the most active molecules in the dataset and identified promising candidates, including FS168. We performed molecular dynamics simulations with FS168 bound to the AChE1 of B. tabaci and observed stabilization and interaction with important catalytic amino acids, indicating a potential inhibition mechanism. Our results showcase the potential of combining molecular modeling and 3D-QSAR approaches for discovering new potential AChE1 inhibitors in Bemisia tabaci as selective agrochemicals.

Background/Objectives: Malaria is a prominent vector-borne disease, with a high mortality rate, particularly in children under five years old. Despite the use of various insecticides for its control, the emergence of resistant mosquitoes poses a significant public health threat. Acetylcholinesterase (AChE) is a crucial enzyme in nerve transmission and a primary target for insecticide development due to its role in preventing repeated nerve impulses. Recent studies have identified difluoromethyl ketone (DFK) as a potent inhibitor of both sensitive and resistant Anopheles gambiae acetylcholinesterase (AgAChE). This study aimed to identify novel AgAChE inhibitors that could be explored for malaria prevention. Methods: We performed a virtual screening on the PubChem database using a pharmacophore model from difluoromethyl ketone-inhibited AgAChE’s crystal structure. The most promising compound was then subjected to molecular docking and dynamics studies with AgAChE to confirm initial findings. ADMET and agrochemical likeness (ag-like) properties were also analyzed to assess its potential as an agrochemical agent. Results: PubChem18463786 was identified as the most suitable compound from the virtual screening. Molecular docking and molecular dynamics studies confirmed its strong interaction with AgAChE. The ADMET and ag-like analyses indicated that PubChem18463786 possesses physicochemical properties suggesting a high probability of non-absorption in humans and meets the criteria for agrochemical similarity. Conclusions: Our findings suggest that PubChem18463786 is a potential AgAChE inhibitor candidate. After validation through in vitro and in vivo experiments, it could be exploited for malaria prevention and serve as a lead compound for the synthesis of new, more effective, and selective agrochemical agents.

Phytopathogenic fungi like Fusarium graminearum are the cause of the disease gibberellosis, also known as Fusarium head blight (FHB). This disease shows significant losses in agriculture and effects on global economy. Nevertheless, this condition can be reduced with the use of commercial fungicides. Thus, this work describes computational studies performed on a group of natural products triazole derivatives using as starting point a small library of quinazolines synthesized by the literature. These quinazolines were applied to build QSAR models. Furthermore, using the Swiss Model server, a comparative modelling of the β-tubulin protein was realized to test the models and the compound 15, a triazole derivative of thymol successfully was further through both the QEPest and ProTox II toxicity tests. The behavior and stability between compound 15 and β-tubulin were then evaluated by 200 ns of molecular dynamics in comparison to carbendazim as standard inhibitor. Finally, the compound 15 revealed a stable complex with the protein throughout the simulation, exhibiting low fluctuations in the RMSF, indicating good interactions with the residues present. The investigation of the free energy of binding supports this, showing that whereas carbendazim had an MM/GBSA of -18 kcal/mol, thymol-derived 15 had an MM/GBSA of -44 kcal/mol.

Introdução: O câncer continua sendo um dos maiores desafios para a saúde global. No Brasil, estimativas para 2023-2025 indicam aproximadamente 704 mil novos casos anuais, com o câncer de mama feminino (CAM) ocupando a segunda posição em incidência (74 mil casos/ano).1 Diante desse cenário, terapias inovadoras são urgentes para melhorar o prognóstico e a qualidade de vida das pacientes. A hiperativação de vias de sinalização intracelular, como a via fosfatidilinositol 3-quinase (PI3K)/proteína quinase B (AKT)/alvo mamífero da rapamicina (mTOR), está associada à progressão tumoral no CAM.2 Essa via regula processos celulares essenciais, como proliferação, metabolismo e apoptose, contribuindo para a carcinogênese.3 Compostos capazes de modular essa via são alvos promissores para o tratamento. A literatura científica apresenta estudos que apontam os efeitos das naftoquinonas na referida neoplasia.4 Objetivo: Dessa forma, o presente trabalho teve como objetivo analisar a capacidade antitumoral de 6 polifenóis naftoquinônicos inéditos (PM-PIR-PANI, PM-PIR-NAF, PM-PIR-SAL, PM-PIR-PNB, PM-MORF-NAF, PM-MORF-SAL) em linhagem de CAM, MDA-MB-231. Os resultados in vitro foram complementados por meio de estudos in silico para investigar e confirmar mecanismos de inibição. Material e Método: Para isso, as células foram cultivadas em meio Roswell Park Memorial Institute (RPMI), mantidas a 37°C e 5% CO2. Então, as células foram semeadas em em placas de 96 poços em concentração de 3x105 células/cm2 e tratadas com concentrações dos compostos entre 10-7 e 10-3M. A viabilidade celular foi avaliada pelo reagente sodium 3’-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro) benzenesulfonic acid combinado ao Metassulfato de fenazina medindo absorbância a 540 nm após 2 horas de incubação. As análises in silico utilizaram o software GOLD 2021.1.0 para simular o acoplamento molecular dos compostos à enzima PI3K. As poses finais foram selecionadas considerando interações com o resíduo Lys833, crítico para a ligação ao domínio catalíticoda PI3K.5 Resultados e Discussão: Os resultados in vitro revelaram que PM-PIR-SAL e PM-PIR-NAF apresentaram maior potência, com valores de IC50 de 1x10-6 M e 3,3x10-6 M, respectivamente. Já as simulações in silico destacaram PM-MORF-NAF e PM-MORF-SAL como os compostos com maior número de interações de hidrogênio (6 e 5 respectivamente) e ligação à Lys833, sugerindo potenciais mecanismos de inibição. Esses achados indicam que os polifenóis naftoquinônicos estudados possuem ação antitumoral promissora, modulando a via PI3K/AKT/mTOR. Conclusões: Conclui-se que os compostos PM-PIR-SAL, PM-PIR-NAF, PM-MORF-NAF e PM-MORF-SAL emergem como candidatos terapêuticos relevantes, abrindo caminho para pesquisas futuras e desenvolvimento de novas estratégias contra o CAM. A combinação de abordagens experimentais e computacionais reforça a importância de métodos multidisciplinares na oncologia, com potencial para acelerar a descoberta de fármacos mais eficazes e seguros.

Glycogen synthase kinase-3 beta (GSK-3β) plays a crucial role in multiple cellular processes and is implicated in different types of cancers and neurological disorders, including Alzheimer’s disease. Despite extensive efforts to develop novel GSK-3β inhibitors, the discovery of potent and selective lead compounds remains a challenge. In this study, we evaluated the GSK-3β inhibitory potential of semisynthetic flavonoid derivatives, which exhibited sub-micromolar activity. To gain further insights, we employed molecular docking, molecular dynamics simulations, and pharmacokinetic profile predictions. The docking studies revealed that the most potent inhibitor, compound 10, establishes key interactions with the ATP-binding site. Molecular dynamics simulations further confirmed that compound 10 maintains stable interactions with GSK-3β throughout the simulation. Additionally, pharmacokinetic predictions identified compound 3 as a promising candidate for Alzheimer’s disease therapy due to its ability to cross the blood–brain barrier. These findings suggest that, within the studied flavonoid derivatives, these compounds (particularly 10 and 3) hold potential as lead compounds for GSK-3β inhibition. The combination of strong enzymatic inhibition, stable binding interactions, and favorable pharmacokinetic properties highlights their promise for further development in cancer and neurodegenerative disease research.

Background: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics. Objective: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. Methods: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. Results: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). Conclusion: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.

Protein kinases (in this case, HER-2 and EGFR) are involved in cancer-related diseases. Some reports have shown unique CoMFA models using the sum of activities expressed as pIC₅₀ (-log IC₅₀), as the classical CoMFA technique would not be the best strategy to construct models for multitarget therapy considering that the molecular alignment will not be the same for different targets. An alternative for this problem is the use of Topomer-CoMFA, a variation of CoMFA, which does not require the alignment step in the generation of 3D models. In this study, we propose the combined use of the sum of activities and Topomer-CoMFA for the construction of a unique dual 3D model considering the inhibitory activities against EGFR and HER-2. For this, 88 compounds from the literature were divided into two groups: training (71) and test (17) sets. The biological activity of each compound, expressed as IC₅₀ for EGFR and HER-2, was transformed into pIC₅₀, summed, and used as the dependent variable in the Topomer-CoMFA analyses. The obtained model was considered statistically robust in the prediction of the dual activity of new compounds. Finally, based on the obtained model, we proposed structural modifications to some of the compounds used to improve the biological data. From the 3D model, we suggested new derivative compounds with improved biological activity for both targets. Therefore, the combination of the techniques proposed in this study proves to be a good strategy to construct better statistical models that can predict biological activities in multitarget systems.