RESUMO
The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including ß-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of ß-lactamases, the primary resistance mechanism associated with ß-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.
Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Animais , Antibacterianos/química , Compostos Aza/química , Compostos Aza/farmacologia , Ciclo-Octanos/química , Ciclo-Octanos/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Pseudomonas aeruginosa/efeitos dos fármacos , beta-LactamasesRESUMO
The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.
Assuntos
Antineoplásicos , Compostos Heterocíclicos , Organofosfonatos , Organofosfonatos/química , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Compostos Aza/química , Compostos Aza/síntese química , Compostos Aza/farmacologia , AnimaisRESUMO
Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure-activity studies using these scaffolds resulted in several leads with promising properties.
Assuntos
Desenho de Fármacos , Inibidores de Integrase de HIV , Integrase de HIV , HIV-1 , Piridonas , Humanos , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Aza/síntese química , Relação Dose-Resposta a Droga , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Estrutura Molecular , Piridonas/química , Piridonas/farmacologia , Piridonas/síntese química , Relação Estrutura-Atividade , Integrases/química , Integrases/metabolismo , Integrases/farmacocinéticaRESUMO
We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI50 = 5.6 ± 1.1 µM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity.
Assuntos
Antineoplásicos , Butirilcolinesterase , Proliferação de Células , Inibidores da Colinesterase , Cumarínicos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Butirilcolinesterase/metabolismo , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/síntese química , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Aza/química , Compostos Aza/farmacologia , Compostos Aza/síntese química , Relação Dose-Resposta a Droga , Neurônios/efeitos dos fármacosRESUMO
Small organic photothermal agents (PTAs) with absorption bands located in the second near-infrared (NIR-II, 1000-1700â nm) window are highly desirable for effectively combating deep-seated tumors. However, the rarely reported NIR-II absorbing PTAs still suffer from a low molar extinction coefficient (MEC, ϵ), inadequate chemostability and photostability, as well as the high light power density required during the therapeutic process. Herein, we developed a series of boron difluoride bridged azafulvene dimer acceptor-integrated small organic PTAs. The B-N coordination bonds in the π-conjugated azafulvene dimer backbone endow it the strong electron-withdrawing ability, facilitating the vigorous donor-acceptor-donor (D-A-D) structure PTAs with NIR-II absorption. Notably, the PTA namely OTTBF shows high MEC (7.21×104â M-1 cm-1), ultrahigh chemo- and photo-stability. After encapsulated into water-dispersible nanoparticles, OTTBF NPs can achieve remarkable photothermal conversion effect under 1064â nm irradiation with a light density as low as 0.7â W cm-2, which is the lowest reported NIR-II light power used in PTT process as we know. Furthermore, OTTBF NPs have been successfully applied for in vitro and in vivo deep-seated cancer treatments under 1064â nm laser. This study provides an insight into the future exploration of versatile D-A-D structured NIR-II absorption organic PTAs for biomedical applications.
Assuntos
Compostos de Boro , Lasers , Terapia Fototérmica , Compostos de Boro/química , Camundongos , Animais , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Dimerização , Estrutura Molecular , Linhagem Celular Tumoral , Compostos Aza/química , Ensaios de Seleção de Medicamentos Antitumorais , Sobrevivência Celular/efeitos dos fármacos , Raios Infravermelhos , Proliferação de Células/efeitos dos fármacosRESUMO
Herein, we report synthesis, characterization, antimicrobial and antimalarial activities of azines Schiff base ligands (L1 -L4 ) and their palladium (II) complexes (C1 -C4 ) of [Pd(L)(OAc)2 ] type. The azine ligands (L1 -L4 ) were prepared by condensation of carbonyl compounds with hydrazine hydrate and their complexes by the reaction of palladium acetate with L1 -L4 ligands in 1 : 1 molar ratio. The prepared ligands and their complexes were characterized by spectral characterization using 1 H &13 C-NMR, FT-IR and mass spectral studies, which revealed that the ligands coordinates via azomethine nitrogen and heteroatom or aryl carbon with palladium. Moreover, Schiff bases and their palladium (II) complexes have been screened for their antibacterial (S. aureus, B. subtillis, and S. typhi, P. aeruginosa), antifungal (C. albicans, A. niger, and A. clavatus) and antimalarial (P. falciparum) activities. The Schiff base L4 showed good results for antibacterial against S. aureus (MIC, 50â µg/mL) and antimalarial against P. falciparum (IC50 , 0.83â µg/mL). The complex C1 showed best antibacterial activity (MIC, 62.5â µg/mL) against S. typhi and the complex C4 exhibited remarkable antimalarial activity (IC50 , 0.42â µg/mL) among the tested compounds. Thus, azines based ligands and their Pd complexes can be good antimicrobial and antimalarial agents if explored further.
Assuntos
Anti-Infecciosos , Antimaláricos , Complexos de Coordenação , Antibacterianos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Antimaláricos/farmacologia , Candida albicans , Complexos de Coordenação/química , Ligantes , Testes de Sensibilidade Microbiana , Paládio/química , Bases de Schiff/química , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus , Compostos Aza/químicaRESUMO
We propose a sensitive, selective, and rapid fluorescent assay for detecting resorcinol (RC) based on its specific chemical reaction with dopamine. Under alkaline condition, RC would react with dopamine to yield fluorescent azamonardine, which emits strong blue fluorescence and has a superior excitation wavelength at 416 nm and an emission wavelength at 461 nm. The azamonardine with a molecular weight of 258.1 confirmed by ICP-MS has a quantum yield of 71.3%. The reaction is completed within 1 min showing great potential for point-of-care testing. This assay showed high sensitivity and had a good relationship between fluorescent intensity at 461 nm and RC concentration (I461 = 106.4 + 93.6*CRC; R2 = 0.9904) over the range of 0-40 µM. More importantly, the assay showed a prominent anti-interference from various substances and even can distinguish RC from its isomers, o-dihydroxybenzene and p-dihydroxybenzene. Finally, our assay successfully quantified RC contents in wheat powder and hair dyes with high accuracy.
Assuntos
Compostos Aza/química , Dopamina/química , Corantes Fluorescentes/química , Resorcinóis/análise , Tinturas para Cabelo/química , Pós/química , Triticum/químicaRESUMO
A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, ß unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity. The majority of the compounds had moderate to potent activity against A549 human lung cancer cells, MDA-MB-231 breast cancer cells, and Hela human cervical cancer cells. Among them, the compound 6d showed the strongest effect on A549 cell line with IC50 of 0.26 µM; the compound 8d showed the strongest cytotoxicity on MDA-MB-231 cell line with IC50 of 0.10 µM; and the compound 6b showed the strongest activity on Hela cell line with IC50 of 0.18 µM.
Assuntos
Antineoplásicos , Compostos Aza/farmacologia , Compostos de Espiro/farmacologia , Antineoplásicos/química , Compostos Aza/química , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Compostos de Espiro/síntese química , Relação Estrutura-AtividadeRESUMO
Necroptosis, a key form of programmed lytic cell death, has gained recognition as an important driver in various inflammatory diseases. Inhibition of kinase activity of receptor interaction protein kinase 1 (RIPK1), which block the activation of the necroptosis pathway has shown therapeutic potential in many human diseases. In order to find new chemotypes of RIPK1 inhibitors, a virtual screening workflow was performed and led to the discovery of 8-benzoyl-3-benzyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (compound 8) as a hit compound. Further structural optimization identified a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 inhibitors. Among them, compound 41 exhibited prominent inhibitory activity against RIPK1 with an IC50 value of 92 nM. Meanwhile, compound 41 showed a significant anti-necroptotic effect in a necroptosis model in U937 cells. Therefore, compound 41 could be employed as a lead compound of RIPK1 inhibitors for further structural optimization.
Assuntos
Compostos Aza , Inibidores de Proteínas Quinases , Proteína Serina-Treonina Quinases de Interação com Receptores , Compostos de Espiro , Humanos , Apoptose , Compostos Aza/química , Compostos Aza/farmacologia , Necroptose , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologiaRESUMO
Aza-BODIPY compounds with methoxy groups at -3 and -5 and triphenylamine moieties at -1 and -7 positions with and without heavy bromine atoms at -2 and -6 positions have been designed and synthesized. The chemical structures of the novel compounds were fully characterized using 1H NMR, 13C NMR, FTIR, and HRMS-TOF-ESI techniques. Steady-state absorption and emission features were investigated to analyze ground-state interactions. The effects of triphenylamine moieties and bromine atoms on charge transfer dynamics and two-photon absorption (TPA) properties were investigated using femtosecond transient absorption spectroscopy measurements and open-aperture (OA) Z-scan experiments, respectively. Contrary to popular belief, the compound containing heavy bromine atoms and triphenylamine moieties did not demonstrate any triplet transition. Since the triphenylamine moiety has high electron-donating properties and a long conjugation length, it exhibited intramolecular charge transfer (ICT) features from electron-donating moieties to the aza-BODIPY core. Additionally, it is concluded that the excited-state lifetime is shortened in the presence of a bromine atom with triphenylamine moieties. This result is rather interesting since the triplet excited state is quenched by the triphenylamine moiety despite the presence of a heavy bromine atom. The performed OA Z-scan experiments revealed that the aza-BODIPY compound containing bromine atoms has a higher TPA cross-section value (116 GM) due to efficient intramolecular charge transfer compared to that without bromine atoms (89 GM). Additionally, in the theoretical calculations, it was found that the charge transfer percentage (CT%) was the strongest in compounds containing bromine atoms.
Assuntos
Compostos Aza , Fármacos Fotossensibilizantes , Fármacos Fotossensibilizantes/química , Bromo , Teoria Quântica , Compostos de Boro/química , Compostos Aza/químicaRESUMO
New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined.
Assuntos
Compostos Aza/síntese química , Derivados de Benzeno/síntese química , Luminescência , Triazóis , Compostos Aza/química , Derivados de Benzeno/química , Elétrons , Triazóis/químicaRESUMO
We introduce a new reagent class, 2-azatrienes, as a platform for catalytic enantioselective synthesis of allylic amines. Herein, we demonstrate their promise by a diastereodivergent synthesis of syn- and anti-1,2-diamines through their Cu-bis(phosphine)-catalyzed reductive couplings with imines. With Ph-BPE as the supporting ligand, anti-diamines are obtained (up to 91% yield, >20:1 dr, and >99:1 er), and with the rarely utilized t-Bu-BDPP, syn-diamines are generated (up to 76% yield, 1:>20 dr, and 97:3 er).
Assuntos
Compostos Aza/química , Cobre/química , Diaminas/química , Compostos Heterocíclicos/química , Catálise , Iminas/química , Conformação Molecular , Oxirredução , EstereoisomerismoRESUMO
We report the first enantioselective total syntheses of the hasubanan alkaloid (-)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found that (-)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.
Assuntos
Alcaloides/síntese química , Alcaloides/química , Compostos Aza/química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Metais/química , EstereoisomerismoRESUMO
A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable ß-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.
Assuntos
Compostos Aza/química , Oligopeptídeos/química , Aldeídos/química , Amino Álcoois/química , Catálise , Radicais Livres/química , Iminas/química , Magnésio/química , Oxirredução , EstereoisomerismoRESUMO
Phosphines have, in combination with transition metals, played a pivotal role in the rapid development of efficient catalytic processes. Caged phosphines constitute a class of three-dimensional scaffolds providing unique control over steric and electronic properties. The versatility of the caged phosphine ligands has been demonstrated elegantly by the groups of Verkade, Gonzalvi as well as Stradiotto. Our research group has also been working extensively for the past several years in the development of 1,3,5-triaza-7-phosphaadamantane-based caged ligands and in this personal note we have summarized these applications pertaining to the modification of biologically useful nucleosides and heteroarenes.
Assuntos
Adamantano/análogos & derivados , Complexos de Coordenação/química , Compostos Heterocíclicos/síntese química , Nucleosídeos/síntese química , Compostos Organofosforados/síntese química , Adamantano/síntese química , Compostos Aza/química , Catálise , Paládio/químicaRESUMO
3,7-Diazabicyclo[3.3.1]nonane scaffold can serve as a basis for the design of molecular switches stimulating the fast release of water soluble compounds under the influence of external factors from the liposomal containers having those switches incorporated into the lipid bilayer. It was demonstrated that liposomes having 3,7-dihexadecyl-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one (3) incorporated into the liposomal membrane sharply increase the permeability upon pH decrease from 7.4 to 6.5, and compound 3 can serve as a pH-sensitive agent in the bilayer of liposomal nanocontainers. Similar but less pronounced effect was shown for liposomes modified with 3,7-bis(methyldodecylaminoacetyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane (5) and 3,7-didodecylsulfonyl-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one (4). The structure (morphology) and size of modified liposomes were studied with scanned transmission electron microscopy.
Assuntos
Compostos Aza/química , Compostos Aza/síntese química , Bicamadas Lipídicas/química , Lipossomos/química , Microscopia Eletrônica de Transmissão , Estrutura MolecularRESUMO
A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.
Assuntos
Compostos Aza/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indóis/farmacologia , Animais , Compostos Aza/síntese química , Compostos Aza/química , Cães , Relação Dose-Resposta a Droga , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indóis/síntese química , Indóis/química , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Herein we present a mononuclear lanthanum(III) complex obtained in a template cyclocondensation reaction of lanthanum(III) nitrate salt, 1,2-propanediamine, and 2,6-diacetylpyridine (LaPA complex). A preliminary investigation of the biological potential of this compound was conducted using a biomedically relevant target Tel26. We found that, different from parallel G4, antiparallel G4, and duplex DNA, only a hybrid-type G4 structure of Tel26 in a K+ solution was significantly stabilized by ≥7 °C, which emerged in our UV melting studies. Moreover, LaPA induced structural changes in the Tel26 structure in a K+-deprived solution, suggesting that it may also lead to conformational changes in "non-G4" telomeric DNA.
Assuntos
Compostos Aza/química , DNA/química , Lantânio/química , Compostos Macrocíclicos/síntese química , Dicroísmo Circular , Ligantes , Compostos Macrocíclicos/química , Microscopia Eletrônica de Varredura , Conformação de Ácido Nucleico , Espectrometria de Massas por Ionização por Electrospray , Difração de Raios XRESUMO
The chemical behavior of steroidal N-sulfonyl-1-azadienes toward carbonyl compounds, in the presence of pyrrolidine, is described. With aldehydes, these azadienes participate in hetero-Diels-Alder reactions with the in situ generated enamines. The stereoselectivity results from the approach of the dienophiles from the less hindered α-face of the steroid, with the pyrrolidine moiety endo and retention of the enamine trans geometry. This diastereoselective synthetic methodology led to a new class of chiral pentacyclic steroids. Interestingly, the studied steroidal scaffolds follow a different mechanistic pathway with cyclic ketones. They undergo a diastereoselective annulation reaction, under enamine catalysis, affording chiral hexacyclic steroids.
Assuntos
Alcenos/química , Aminas/química , Compostos Aza/química , Esteroides/química , Catálise , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Esteroides/síntese químicaRESUMO
Many molecular simulation methods use force fields to help model and simulate molecules and their behavior in various environments. Force fields are sets of functions and parameters used to calculate the potential energy of a chemical system as a function of the atomic coordinates. Despite the widespread use of force fields, their inadequacies are often thought to contribute to systematic errors in molecular simulations. Furthermore, different force fields tend to give varying results on the same systems with the same simulation settings. Here, we present a pipeline for comparing the geometries of small molecule conformers. We aimed to identify molecules or chemistries that are particularly informative for future force field development because they display inconsistencies between force fields. We applied our pipeline to a subset of the eMolecules database, and highlighted molecules that appear to be parameterized inconsistently across different force fields. We then identified over-represented functional groups in these molecule sets. The molecules and moieties identified by this pipeline may be particularly helpful for future force field parameterization.