Fluorinated benzoxazinones designed via MIA-QSAR, docking and molecular dynamics as protoporphyrinogen IX oxidase inhibitors.

BACKGROUND: Fluorine plays a significant role in agrochemical science because approximately 25% of herbicides licensed worldwide contain this element. In a pool of previously synthesized benzoxazinones, some compounds contained fluorine and demonstrated inhibitory activities against protoporphyrinogen IX oxidase (PPO). Therefore, three data sets of benzoxazinone derivatives with known inhibitory activity against PPO were employed to build a multivariate image analysis applied to a quantitative structure-activity relationships (MIA-QSAR) model to identify improved analogs with at least one fluorine substituent. RESULTS: The QSAR model was vigorously validated and demonstrated to be highly predictive (r2 = 0.85, q2 = 0.71, and r2 pred = 0.88); thus, the model can provide reliable estimations for the PPO inhibitory activity of unknown derivatives. From these compounds, a couple of N-substituted benzoxazinones that contained the -CH2CHF2 group were found with predicted pKi values larger than 8 (Ki in mol L-1) and higher lipophilicity than the most active data set compounds. In addition, we carried out a systematic investigation of the binding mode of PPO by performing computational docking followed by molecular dynamics simulations. The proposed binding mode was consistent with experimental studies, and several potential key residues were identified. CONCLUSION: Two new proposed benzoxazinones exhibited better performance than compounds of the data set, and fluorine substituents played pivotal roles in describing the biological activities. © 2024 Society of Chemical Industry.

Enhanced Sampling in Molecular Dynamics Simulations: How Many MD Snapshots can be Needed to Reproduce the Biological Behavior?

Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.

Vanadium complex as a potential modulator of the autophagic mechanism through proteins PI3K and ULK1: development, validation and biological implications of a specific force field for [VO(bpy)2Cl].

The modulation of autophagy has been presented as a very useful strategy in anticancer treatments. In this sense, the vanadium complex (VC) bis(2,2'-bipyridine)chlorooxovanadium(IV), [VO(bpy)2Cl], is known for its ability to induce autophagy in triple-negative breast cancer cells (TNBC). An excellent resource to investigate the role of VC in the induction of autophagy is to make use of Molecular Dynamics (MD) simulations. However, until now, the scarcity of force field parameters for the VC prevented a reliable analysis. The autophagy signaling pathway starts with the PI3K protein and ends with ULK1. Therefore, in the first stage of this work, we developed a new AMBER force field for the VC (VCFF) from a quantum structure, obtained by DFT calculations. In the second stage, the VCFF was validated through structural analyses. From this, it was possible to investigate, through docking and MD (200 ns), the performance of the PI3K-VC and ULK1-VC systems (third stage). The analyses of this last stage involved RMSD, hydrogen bonds, RMSF and two pathways for the modulation of autophagy. In general, this work fills in the absence of force field parameters (FF) for VC by proposing an efficient and new FF, in addition to investigating, at the molecular level, how VC is able to induce autophagy in TNBC cells. This study encourages new parameterizations of metallic complexes and contributes to the understanding of the duality of autophagic processes.Communicated by Ramaswamy H. Sarma.

Silver(I) and Copper(II) 1,10-Phenanthroline-5,6-dione Complexes as Promising Antivirulence Strategy against Leishmania: Focus on Gp63 (Leishmanolysin).

Leishmaniasis, caused by protozoa of the genus Leishmania, encompasses a group of neglected diseases with diverse clinical and epidemiological manifestations that can be fatal if not adequately and promptly managed/treated. The current chemotherapy options for this disease are expensive, require invasive administration and often lead to severe side effects. In this regard, our research group has previously reported the potent anti-Leishmania activity of two coordination compounds (complexes) derived from 1,10-phenanthroline-5,6-dione (phendione): [Cu(phendione)3].(ClO4)2.4H2O and [Ag(phendione)2].ClO4. The present study aimed to evaluate the effects of these complexes on leishmanolysin (gp63), a virulence factor produced by all Leishmania species that plays multiple functions and is recognized as a potential target for antiparasitic drugs. The results showed that both Ag-phendione (-74.82 kcal/mol) and Cu-phendione (-68.16 kcal/mol) were capable of interacting with the amino acids comprising the active site of the gp63 protein, exhibiting more favorable interaction energies compared to phendione alone (-39.75 kcal/mol) or 1,10-phenanthroline (-45.83 kcal/mol; a classical gp63 inhibitor) as judged by molecular docking assay. The analysis of kinetic parameters using the fluorogenic substrate Z-Phe-Arg-AMC indicated Vmax and apparent Km values of 0.064 µM/s and 14.18 µM, respectively, for the released gp63. The effects of both complexes on gp63 proteolytic activity were consistent with the in silico assay, where Ag-phendione exhibited the highest gp63 inhibition capacity against gp63, with an IC50 value of 2.16 µM and the lowest inhibitory constant value (Ki = 5.13 µM), followed by Cu-phendione (IC50 = 163 µM and Ki = 27.05 µM). Notably, pretreatment of live L. amazonensis promastigotes with the complexes resulted in a significant reduction in the expression of gp63 protein, including the isoforms located on the parasite cell surface. Both complexes markedly decreased the in vitro association indexes between L. amazonensis promastigotes and THP-1 human macrophages; however, this effect was reversed by the addition of soluble gp63 molecules to the interaction medium. Collectively, our findings highlight the potential use of these potent complexes in antivirulence therapy against Leishmania, offering new insights for the development of effective treatments for leishmaniasis.

Parameterization and validation of a new AMBER force field for an oxovanadium (IV) complex with therapeutic potential implications in Alzheimer's disease.

The scarcity of efficient force fields to describe metal complexes may be a problem for new advances in medicinal chemistry. Thus, the development of force fields for these compounds can be valuable for the scientific community, especially when it comes to molecules that show interesting outputs regarding potential treating of diseases. Vanadium complexes, for instance, have shown promising results towards therapeutics of Alzheimer's Disease, most notably the bis(maltolato)oxovanadium (IV). Therefore, the mainly goal of this work is to develop and validate a new set of parameters for this vanadium complex from a minimum energy structure, obtained by DFT calculations, where great results of the new force field are found when confronted with experimental and quantum reference values. Moreover, the new force field showed to be quite effective to describe the molecule of under study whilst GAFF could not describe it effectively. In addition, a case study points out hydrogen bonds in the vanadium complex-PTP1B system.

Multivariate image analysis applied to quantitative structure-activity relationships and docking studies of recent hydroxyphenylpyruvate deoxygenase inhibitors.

BACKGROUND: Mesotrione is a triketone widely used as an inhibitor of the hydroxyphenylpyruvate deoxygenase (HPPD) enzyme. However, new agrochemicals should be developed continuously to tackle the problem of herbicide resistance. Two sets of mesotrione analogs have been synthesized recently and they have demonstrated successful phytotoxicity against weeds. In this study, these compounds were joined to form a single data set and the HPPD inhibition of this enlarged library of triketones was modeled using multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR). Docking studies were also carried out to validate the MIA-QSAR findings and to aid the interpretation of ligand-enzyme interactions responsible for the bioactivity (pIC50 ). RESULTS: The MIA-QSAR models based on van der Waals radii (rvdW ), electronegativity (ε), and the rvdW /ε ratio as molecular descriptors were both predictive to an acceptable degree (r2 ≥ 0.80, q2 ≥ 0.68 and r2 pred ≥ 0.68). Subsequently, partial least squares (PLS) regression parameters were applied to predict the pIC50 values of newly proposed derivatives, yielding a few promising agrochemical candidates. The calculated log P for most of these derivatives was found to be higher than that of mesotrione and the library compounds, indicating that they should be less prone to leach out and contaminate groundwater. CONCLUSION: Multivariate image analysis descriptors corroborated by docking studies were capable of modeling the herbicidal activities of 68 triketones reliably. Due to the substituent effects at the triketone framework, particularly of a nitro group in R3 , promising analogs could be designed. The P9 proposal demonstrated higher calculated activity and log P than commercial mesotrione. © 2023 Society of Chemical Industry.

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)-protein interactions, parameterization, and validation of a new force field.

Autophagy has drawn attention from the scientific community, mainly because of its significant advantages over chemotherapeutic processes. One of these advantages is its direct action on cancer cells, avoiding possible side effects, unlike chemotherapy, which reaches tumor cells and affects healthy cells in the body, leading to a great loss in the quality of life of patients. In this way, it is known that vanadium complex (VC) [VO(oda)(phen)] has proven inhibition effect on autophagy process in pancreatic cancer cells. Keeping that in mind, molecular dynamics (MD) simulations can be considered excellent strategies to investigate the interaction of metal complexes and their biological targets. However, simulations of this type are strongly dependent on the appropriate choice of force field (FF). Therefore, this work proposes the development of AMBER FF parameters for VC, having a minimum energy structure as a starting point, obtained through DFT calculations with B3LYP/def2-TZVP level of theory plus ECP for the vanadium atom. An MD simulation in vacuum was performed to validate the developed FF. From the structural analyses, satisfying values of VC bond lengths and angles were obtained, where a good agreement with the experimental data and the quantum reference was found. The RMSD analysis showed an average of only 0.3%. Finally, we performed docking and MD (120 ns) simulations with explicit solvent between VC and PI3K. Overall, our findings encourage new parameterizations of metal complexes with significant biological applications, as well as allow to contribute to the elucidation of the complex process of autophagy.

Molecular Dynamics-Assisted Interaction of Vanadium Complex-AMPK: From Force Field Development to Biological Application for Alzheimer's Treatment.

A large part of the world's population is affected by Alzheimer's disease (AD) and diabetes mellitus type 2, which cause both social and economic impacts. These two conditions are associated with one protein, AMPK. Studies have shown that vanadium complexes, such as bis(N',N'-dimethylbiguanidato)-oxovanadium(IV), VO(metf)2·H2O, are potential agents against AD. A crucial step in drug design studies is obtaining information about the structure and interaction of these complexes with the biological targets involved in the process through molecular dynamics (MD) simulations. However, MD simulations depend on the choice of a good force field that could present reliable results. Moreover, general force fields are not efficient for describing the properties of metal complexes, and a VO(metf)2·H2O-specific force field does not yet exist; thus, the proper development of a parameter set is necessary. Furthermore, this investigation is essential and relevant given the importance for both the scientific community and the population that is affected by this neurodegenerative disease. Therefore, the present work aims to develop and validate the AMBER force field parameters for VO(metf)2·H2O since the literature lacks such information on metal complexes and investigate through classical molecular dynamics the interactions made by the complex with the protein. The proposed force field proved to be effective for describing the vanadium complex (VC), supported by different analyses and validations. Moreover, it had a great performance when compared to the general AMBER force field. Beyond that, MD findings provided an in-depth perspective of vanadium complex-protein interactions that should be taken into consideration in future studies.

Exploring electronic, structural and dynamics parameters of phenylbenzothiazole complexes with Mn2+, Cu2+ and Zn2+ for designing new magnetic resonance imaging (MRI) probes: congruence between computation and spectroscopic data.

Cancer is one of the leading causes of human death worldwide, being one of the most serious problems faced by mankind. For the diagnosis, Magnetic Resonance Imaging (MRI), through effective contrast agents (Cas), has greatly helped in the diagnosis at the initial stages. However, it is necessary to include new compounds more effective and selective for cancer diagnosis. The complexes with Mn2+, Cu2+ and Zn2+ have received great attention due to their applications as CAs for MRI. Those materials can shorten the T2 and T2* transverse relaxation times. Thus, the representative structures for hyperfine coupling constants (HFCCs) were selected from docking results by frequency of occupancy calculations. From the Multivariate Analysis to obtain the PCA graphs in the choice of a representative conformations. it is possible to notice that the variable energy does not present a high correlation with the other variables, and structural factors, such as the spatial positions of the metal atoms, seem to be important in the reactivity of the complexes. Structural factors, such as the spatial positions of the metal atoms, seem to be important in the reactivity of the complexes. Theoretical findings suggest that the compounds are capable of increasing the Aiso values of the water molecules, but the complex [Zn(H2O)(NNO)] shows a greater influence, being more sensitive to the Electron paramagnetic resonance parameters than the complexes [CuCl(H2O)NNO] and [MnCl2(H2O)(NNO)] with the explicit solvent and the enzyme. MRI contrast agents have generated various problems due to their high toxicity. In this perspective, this compound may be a promising alternative for transporting the CAs into diseased tissue.Communicated by Ramaswamy H. Sarma.

MIA-QSAR study of the structural merging of (thio)benzamide herbicides with photosynthetic system II inhibitory activities.

Benzamide herbicides consist of a class of photosynthetic system II (PSII) inhibitors widely used for weed control. However, the development of resistance by these weeds to the known herbicides requires an ongoing search for new agrochemicals. We report the combination of two congeneric series of (thio)benzamide herbicides into a single data set and subsequent modeling of their herbicidal activities against PSII using MIA-QSAR. The robust and predictive models were used to estimate the pIC50 of new agrochemical candidates, which were proposed based on a chemical mixing of the substructures of the most active compounds present in the data set. The chemical features affecting the herbicidal activities were analyzed using MIA contour maps, whereas the ligand-enzyme interactions responsible for the binding affinities were rationalized through docking studies. The proposed compound possessing a thiobenzamide moiety and C-11 chain, H, NO2, OH, and OH as variable substituents was the most promising alternative.Communicated by Ramaswamy H. Sarma.

Assessing the Therapeutic and Toxicological Profile of Novel Acetylcholinesterase Reactivators: Value of In Silico And In Vitro Data.

Organophosphorus compounds (OP) make up an important class of inhibitors, mostly employed as pesticides, even as chemical weapons. These toxic substances act through the inhibition of the acetylcholinesterase (AChE) enzyme, which results in elevated synaptic acetylcholine (ACh) levels, leading to serious adverse effects under the cholinergic syndrome. Many reactivators have been developed to combat the toxic effects of these AChE inhibitors. In this line, the oximes highlight because of their good reactivating power of cholinesterase enzymes. To date, no universal antidotes can reactivate AChE inhibited by any OP agent. This review summarizes the intoxication process by neurotoxic OP agents, along with the development of reactivators capable of reversing their effects, approaching aspects like the therapeutic and toxicological profile of these antidotes. Computational methods and conscious in vitro studies, capable of significantly predicting the toxicological profile of these drug candidates, might support the process of development of these reactivators before entering in vivo studies in animals, and then clinical trials. These approaches can assist in the design of safer and more effective molecules, reducing related cost and time for the process.

Exploring 129Xe NMR parameters for structural investigation of biomolecules: relativistic, solvent, and thermal effects.

In recent years, the study of new probes has aroused great interest in the scientific community around the world. Therefore, in the present work, we present a potential candidate for a new spectroscopic probe, the Xe(CO)3(NNO) conjugated to 2-(4'-aminophenyl) benzothiazole complex, XeABT. For this proposal, chemical shift calculations at the DFT level were performed; thus, a factorial design was carried out in order to choose the best computational method. The best combination was the base function ZORA-def2-TZVP, with the functional PBE0 and considering the relativistic effects with the ZORA implementation. Our findings reveal that the 129Xe chemical shifts are affected by thermal and solvent effects, and considering an enzymatic environment, a significant decrease in δ(129Xe) values is observed, suggesting with the XeABT complex it may be a promising spectroscopic probe.

Improved Protocol for the Selection of Structures from Molecular Dynamics of Organic Systems in Solution: The Value of Investigating Different Wavelet Families.

Wavelets are mathematical tools used to decompose and represent another function described in the time domain, allowing the study of each component of the original function with a scale-compatible resolution. Thus, these transforms have been used to select conformations from molecular dynamics (MD) trajectories in systems of fundamental and technological interest. Recently, our research group has used wavelets to develop and validate a method, meant to select structures from MD trajectories, which we named OWSCA (optimal wavelet signal compression algorithm). Here, we moved forward on this project by demonstrating the efficacy of this method on the study of three different systems (non-flexible organic, flexible organic, and protein). For each system, 93 wavelets were investigated to verify which is the best one for a given organic system. The results show that the best wavelets were different for each system and, also, very close to the experimental values, with the wavelets db1, rbio 3.1, and bior1.1 being selected for the non-flexible, flexible organic, and protein systems, respectively. This reinforces our OWSCA as a very efficient and promising method for the selection of structures from MD trajectories of different classes of compounds. Our findings also point out that additional studies considering wavelet families are needed for defining the best wavelet for representing each system under study.

In silico modeling of the AHAS inhibition of an augmented series of pyrimidine herbicides and design of novel derivatives.

Pyrimidine compounds comprise a class of acetohydroxyacid synthase (AHAS) inhibitors, thus possessing herbicidal activity. Due to the ongoing development of resistance by weeds to current herbicides, the design of new agrochemical candidates is often required. This work reports the proposition of unprecedented pyrimidines as herbicides guided by quantitative structure-activity relationship (QSAR) modeling. Multivariate image analysis (MIA) descriptors for 66 pyrimidine derivatives obtained from different sources were regressed against inhibitory activity data, and the resulting QSAR models were found to be reliable and predictive (r2 = 0.88 ± 0.07, q2 = 0.53 ± 0.06, and r2pred = 0.51 ± 0.10 in a bootstrapping experiment using electronegativity-based descriptors). The chemical features responsible for the herbicidal activities were analyzed through MIA contour maps that describe the substituent effects on the response variables, whereas the interaction between the proposed compounds and AHAS was analyzed through docking studies. From the proposed compounds, at least five pyrimidine derivatives exhibited promising performance as AHAS inhibitors compared to the known analogs.

Insights into the value of statistical models, solvent, and relativistic effects for investigating Re complexes of 2-(4'-aminophenyl)benzothiazole: a potential spectroscopic probe.

Cancer affects a major part of the worldwide population, and, to minimize deaths, the diagnosis in the early stages of the disease is fundamental. Thus, to improve diagnosis and treatment new potential spectroscopic probes are crucial. Benzothiazole derivates present antitumor properties and are highly selective and interact strongly with the enzyme phosphoinositide 3-kinase (PI3K), which was associated with cell proliferation and breast cancer cells. In this paper, the rhenium shielding tensors (187Re(σ)) and hydrogen and carbon chemical shifts (1H(δ) and 13C(δ)) of the Re(CO)3(NNO) complex conjugated with 2-(4'-aminophenyl)benzothiazole (ReABT) were evaluated. A statistical HCA model was used to analyze the best DFT protocol to compute σ and δ values and to evaluate the relativistic effects, both in the basis set and Hamiltonian as well as the functionals M06L or PBE0. The best protocol was applied to obtain 187Re(σ) of the ReABT complex in different environments (gas phase, solution, and in the active site of the PI3K enzyme). The results point out that 187Re(σ) values of the ReABT complex change significantly when the complex is docked in the PI3K enzyme.

Computer-Assisted Improvement of Sulfonylureas with Antifungal Properties and Limited Herbicidal Activity: Potential Application in Forage Conservation.

This work reports studies at the molecular level of a series of modified sulfonylureas to determine the chemophoric sites responsible for their antifungal and herbicidal activities. For forage conservation, high antifungal potency and low phytotoxicity are required. A molecular modeling study based on multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) was performed to model these properties, as well as to guide the design of new agrochemical candidates. As a result, the MIA-QSAR models were reliable, robust, and predictive; for antifungal activity, the averages of the main validation parameters were r2 = 0.936, q2 = 0.741, and r2pred = 0.720, and for herbicidal activity, the model was very predictive (r2pred = 0.981 and r2m = 0.944). From the interpretation of the MIA-plots, 46 novel sulfonylureas with likely improved performance were proposed, from which 9 presented promising calculated selectivity indexes. Docking studies were performed to validate the QSAR predictions and to understand the interaction mode of the proposed ligands with the acetohydroxyacid synthase enzyme.

QSAR-Guided Proposition of N-(4-methanesulfonyl)Benzoyl-N'-(Pyrimidin-2-yl)Thioureas as Effective and Safer Herbicides.

Chlorinated agrochemicals play a major role in toxicity due especially to the labile C - Cl bond and high lipophilicity of organochlorines. In turn, urea and thiourea herbicides are widely used for weed control. A series of substituted N-benzoyl-N'-pyrimidin-2-yl thioureas has been recently synthesized and tested against Brassica napus L., demonstrating promising herbicidal activities, particularly for chlorinated derivatives. We have therefore modeled these activities using multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) to find out a significant and reliable correlation between measured and predicted inhibition of B. napus L. root growth (%) and, ultimately, to propose effective, non-chlorinated and/or less lipophilic N-(4-methanesulfonyl)benzoyl-N'-(pyrimidin-2-yl)thiourea candidates. The model was found to be predictive, giving an average r2pred in the external validation of 0.833. The predicted data for the proposed herbicides, interpreted in terms of MIA-plots of the chemical moieties responsible for bioactivity and supported by docking studies towards the photosystem II enzyme, suggest that substituents at both R1 and R2 positions modulate the agrochemical (R1 = Cl increases and R2 = OR decreases bioactivity) and environmental friendship (particularly with R2 = OH) performances of this class of compounds.

Value of Contrast-enhanced Magnetic Resonance Imaging (MRI) in the Diagnosis of Breast Cancer.

This review article aims to address the main features of breast cancer. Thus, the general aspects of this disease have been shown since the first evidence of breast cancer in the world until the numbers today. In this way, there are some ways to prevent breast cancer, such as the woman's lifestyle (healthy eating habits and physical activities) that helps to reduce the incidence of this anomaly. The first noticeable symptom of this anomaly is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer are discovered when the woman feels a lump being present and about 90% of the cases, the cancer is noticed by the woman herself. Currently, the most used method for the detection of cancer and other injuries is the Magnetic Resonance Imaging (MRI) technique. This technique has been shown to be very effective, however, for a better visualization of the images, Contrast Agents (CAs) are used, which are paramagnetic compounds capable of increasing the relaxation of the hydrogen atoms of the water molecules present in the body tissues. The most used CAs are Gd3+ complexes, although they are very efficient, they are toxic to the organism. Thus, new contrast agents have been studied to replace Gd3+ complexes; we can mention iron oxides as a promising substitute.

Understanding the Interaction Modes and Reactivity of Trimedoxime toward MmAChE Inhibited by Nerve Agents: Theoretical and Experimental Aspects.

Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE-OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE-VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes.

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016-2019).

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.