RESUMO
Molecular interaction fields (MIFs) are three-dimensional interaction maps that describe the intermolecular interactions expected to be formed around target molecules. In this paper, a method for the fast computation of MIFs using the approximation functions of quantum mechanics-level MIFs of small model molecules is proposed. MIF functions of N-methylacetamide with chlorobenzene, bromobenzene, and iodobenzene probes were precisely approximated and used to calculate the MIFs on protein surfaces. This method appropriately reproduced halogen-bond-formable areas around the ligand-binding sites of proteins, where halogen bond formation was suggested in a previous study.
Assuntos
Halogênios , Modelos Moleculares , Proteínas , Proteínas/química , Proteínas/metabolismo , Halogênios/química , Acetamidas/química , Teoria Quântica , Clorobenzenos/química , Conformação Proteica , Propriedades de Superfície , Iodobenzenos/química , Sítios de Ligação , Bromobenzenos/química , LigantesRESUMO
Glutaminase converts glutamine into glutamic acid and has two isoforms: glutaminase 1 (GLS1) and glutaminase 2 (GLS2). GLS1 is overexpressed in several tumors, and research to develop glutaminase inhibitors as antitumor drugs is currently underway. The present study examined candidate GLS1 inhibitors using in silico screening and attempted to synthesize novel GLS1 inhibitors and assess their GLS1 inhibitory activities in a mouse kidney extract and against recombinant mouse and human GLS1. Novel compounds were synthesized using compound C as the lead compound, and their GLS1 inhibitory activities were evaluated using the mouse kidney extract. Among the derivatives tested, the trans-4-hydroxycyclohexylamide derivative 2j exhibited the strongest inhibitory activity. We also assessed the GLS1 inhibitory activities of the derivatives 2j, 5i, and 8a against recombinant mouse and human GLS1. The derivatives 5i and 8a significantly decreased the production of glutamic acid at 10 mM. In conclusion, we herein identified two compounds that exhibited GLS1 inhibitory activities with equal potencies as known GLS1 inhibitors. These results will contribute to the development of effective novel GLS1 inhibitors with more potent inhibitory activity.
Assuntos
Ácido Glutâmico , Glutaminase , Humanos , Camundongos , Animais , Linhagem Celular Tumoral , Glutamina , Relação Estrutura-AtividadeRESUMO
Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (-)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.
Assuntos
Antagonistas dos Receptores de Orexina , Animais , Compostos Heterocíclicos de 4 ou mais Anéis , Camundongos , Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina , Orexinas , Relação Estrutura-AtividadeRESUMO
Since PA-8 (5-(4-(Allyloxy)-3-methoxyphenyl)-2-amino-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) was recently identified as a novel small-molecule antagonist of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor, a series of pyrido[2,3-d]pyrimidine derivatives have been designed, synthesized and subsequently evaluated for antagonistic activity on the PAC1 receptor. In this study, we synthesized 21 derivatives based on the PA-8 structure. Among them, the compound 2o (2-Amino-5-(3-trifluoromethoxy-phenyl)-5,8-dihydro-3H,6H-pyrido[2,3-d]pyrimidine-4,7-dione) showed more potent antagonistic activities than PA-8. Intrathecal (i.t.) injection of 2o blocked the induction of PACAP-induced aversive behaviors and mechanical allodynia in mice, and the effects were more potent than those of PA-8. A single i.t. injection of 2o also inhibited spinal nerve ligation (SNL)-induced mechanical allodynia. Repeated intraperitoneal administration of 2o gradually reduced the SNL-induced mechanical allodynia, and this effect appeared earlier than for PA-8. In addition, 2o exhibited a favorable ADME and pharmacokinetics profiles. These results suggest that 2o may become an analgesic for the treatment of neuropathic pain.
Assuntos
Neuralgia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Animais , Hiperalgesia , Camundongos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Pirimidinas/farmacologiaRESUMO
The κ opioid receptor (KOR) is one of the promising targets to develop analgesics lacking morphine like side effects. To seek a novel KOR agonist we designed 6-amide derivatives with an oxabicyclo[3.2.1]octane structure based on a proposed active conformation of a selective KOR agonist nalfurafine. All the synthesized compounds strongly bound to the KOR and some compound showed KOR selectivities. 6R-Amides were more potent and efficacious KOR agonists than the corresponding 6S-isomers. However, most 6-amide derivatives were partial KOR agonist. Conformational analyses of 6R- and 6S-amide derivatives and nalfurafine well accounted for the difference of KOR agonistic activities between two diastereomers. Surprisingly, the tested N-H amides were full δ opioid receptor (DOR) agonists. Among the tested compounds 7a with benzamide moiety was the most potent dual DOR/KOR agonist. On the other hand, 6S-phenylacetamide 8b was potent full DOR agonist with less efficacious agonist activity for the µ receptor and KOR. 6-Amide derivatives with an oxabicyclo[3.2.1]octane structure were expected to be a promising fundamental skeleton for the dual DOR/KOR agonists and/or selective DOR agonists.
Assuntos
Analgésicos/farmacologia , Morfinanos/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides kappa/agonistas , Analgésicos/síntese química , Analgésicos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Morfinanos/síntese química , Morfinanos/química , Relação Estrutura-AtividadeRESUMO
The emergence of drug-resistant bacteria has become a major problem worldwide. Bacterial dipeptidyl peptidases 7 and 11 (DPP7s and DPP11s), belonging to the family-S46 peptidases, are important enzymes for bacterial growth and are not present in mammals. Therefore, specific inhibitors for these peptidases are promising as potential antibiotics. While the molecular mechanisms underlining strict specificity at the S1 subsite of S46 peptidases have been well studied, those of relatively broad preference at the S2 subsite of these peptidases are unknown. In this study, we performed structural and biochemical analyses on DPP7 from Stenotrophomonas maltophilia (SmDPP7). SmDPP7 showed preference for the accommodation of hydrophobic amino acids at the S2 subsite in general, but as an exception, also for asparagine, a hydrophilic amino acid. Structural analyses of SmDPP7 revealed that this exceptional preference to asparagine is caused by a hydrogen bonding network at the bottom of the S2 subsite. The residues in the S2 subsite are well conserved among S46 peptidases as compared with those in the S1 subsite. We expect that our findings will contribute toward the development of a universal inhibitor of S46 peptidases.
Assuntos
Asparagina/química , Dipeptidil Peptidases e Tripeptidil Peptidases/química , Stenotrophomonas maltophilia/enzimologia , Sequência de Aminoácidos , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Interações Hidrofóbicas e Hidrofílicas , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Especificidade por Substrato , TermodinâmicaRESUMO
Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).
Assuntos
Membro C3 da Família 1 de alfa-Ceto Redutase/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Células PC-3 , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We have recently reported that N-alkyl and N-acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the N-substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially different positions compared with those in the alkylamine and amide moieties. Among the tested compounds, cyclopropylsulfonamide 9f (SYK-839) was the most potent full inverse agonist for the DOR, whereas phenethylsulfonamide 9e (SYK-901) showed full DOR agonist activity with moderate potency. These NTI derivatives are expected to be useful compounds for investigation of the molecular mechanism inducing these functional activities.
Assuntos
Naltrexona/análogos & derivados , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Animais , Células CHO , Cricetulus , Humanos , Naltrexona/síntese química , Naltrexona/química , Naltrexona/farmacologia , Receptores Opioides delta/genéticaRESUMO
Nonconventional noncovalent interactions such as CH/O, CH/π, and halogen bonds play important roles in molecular recognition in biological systems and have been increasingly exploited in structure-based drug design. In silico approaches that consider these interactions would be an effective strategy for drug discovery. The computation of the molecular interaction field (MIF), which is a three-dimensional (3D) potential map describing the interactions formed around a target compound, would assist the design of molecules that bind to the target biomolecule via nonconventional interactions. In this study, we developed a novel MIF calculation method that describes nonconventional interactions. This method evaluates the MIF as the interaction energy between the target ligand molecule and probe molecule. To describe the nonconventional interactions, our method employs quantum chemical calculations with four types of probe molecules. The calculated MIFs for casein kinase 2 (CK2) inhibitors correctly identify the halogen bond, CH/π, and CH/O interactions formed in the CK2/inhibitor complexes. Additionally, we have developed a method for calculating the protein-ligand interaction energy (Eint) based on the MIF and a coarse-grained protein model. The calculated interaction energies for CK2 inhibitors correlate with the experimental log(Ki) values. Thus, MIF and Eint obtained by our method show promise as descriptors for protein-ligand interaction prediction by considering nonconventional noncovalent interactions.
Assuntos
Desenho de Fármacos , Halogênios , Simulação por Computador , Descoberta de Drogas , LigantesRESUMO
We recently identified novel small-molecule antagonists of the PACAP type I (PAC1) receptor using docking-based in silico screening followed by in vitro/vivo pharmacological assays. In the present study, we synthesized 18 novel derivatives based on the structure of PA-9, a recently developed antagonist of the PAC1 receptor, with a view to obtain a panel of compounds with more potent antagonistic and analgesic activities. Among them, compound 3d showed improved antagonistic activities. Intrathecal injection of 3d inhibited both pituitary adenylate cyclase-activating polypeptide (PACAP) and spinal nerve ligation-induced mechanical allodynia. The effects were more potent than PA-9. Compound 3d also showed anti-allodynic effects following oral administration. Hence, our results suggest that 3d may become an orally available analgesic in the treatment of the neuropathic pain.
Assuntos
Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Neuralgia/metabolismo , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11.
Assuntos
Benzoatos/farmacologia , Ácido Cítrico/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/química , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Porphyromonas gingivalis/enzimologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Benzoatos/química , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Cristalografia por Raios X , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Fosfatos de Inositol , Modelos Moleculares , Conformação ProteicaRESUMO
Marine tricyclic alkaloids lepadiformine and fasicularin, with a unique perhydropyrrolo[2,1- j]quinoline or perhydropyrido[2,1- j]quinoline framework, were synthesized starting from the B ring of the tricyclic system. This approach includes a highly stereocontrolled diallylation of a cyclic enaminoester and subsequent ring-closing metathesis to construct the A/B ring system, which was transformed into key lactams 32 and 33, and amino alcohol 37. Thus, we achieved formal syntheses of (-)-lepadiformines A, C, and (-)-fasicularin in a divergent manner.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Tiocianatos/química , Tiocianatos/síntese química , Técnicas de Química Sintética , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6ß-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6ß-derivatives.
Assuntos
Morfinanos/química , Morfinanos/farmacologia , Antagonistas dos Receptores de Orexina/química , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Desenho de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Receptores de Orexina/químicaRESUMO
The effect of the acetyl groups of cellulose acetate (CA) on its intrinsic birefringence and its wavelength dependence was investigated using density functional theory (DFT). Seven types of CA repeating-unit models that differ in their degree of substitution (DS) and substitution sites were used in the calculations. The results suggested that the intrinsic birefringence (Δn°) and its wavelength dependence significantly depended on the conformations of the acetyl group at C6. Additionally, the intrinsic birefringence of CA films was estimated as the ensemble average of the calculated Δn° values of the conformers. The increase in the DS of CA led to a more negative intrinsic birefringence and a larger wavelength dependence. The computational results were in good qualitative agreement with the experimental results and suggested that conformational variety and/or its control would be important factors for the design of optical films containing CA.
RESUMO
Formation of 15-membered azalactone by double reductive amination was analyzed using molecular mechanics and density functional theory calculations for simplified model compounds. As a result, the following aspects were clarified. When methylamine attacks a linear bis-aldehyde in the first step, there are possibilities that two regioisomers are formed. However, one of them exhibited remarkably stable energy level compared with the other. The stable isomer indicated a short distance between a methylamine moiety and an unreacted aldehyde. This short distance, about 2.3 Å, could be explained by hydrogen bonding, which implied relatively easy cyclization in the second step. Moreover, this cyclization process was supposed to be exothermic according to comparison of energy levels before and after cyclization.
Assuntos
Lactonas/síntese química , Aldeídos , Aminação , Biologia Computacional , Ciclização , Teoria da Densidade Funcional , Ligação de Hidrogênio , Modelos Moleculares , EstereoisomerismoRESUMO
The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.
Assuntos
Morfinanos/química , Antagonistas dos Receptores de Orexina/química , Sulfonamidas/química , Conformação Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Morfinanos/síntese química , Antagonistas dos Receptores de Orexina/síntese química , Estereoisomerismo , Sulfonamidas/síntese químicaRESUMO
Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are present in the spinal dorsal horn and dorsal root ganglia, suggesting an important role of PACAP signaling systems in the modulation of spinal nociceptive transmission. Previously, we found that intrathecal injection of PACAP or maxadilan, a selective PACAP type I (PAC1) receptor agonist, induced transient aversive responses followed by a long-lasting mechanical allodynia in mice, suggesting that PACAP-PAC1 receptor systems are involved in chronic pain and that selective PAC1 antagonists may become a new class of analgesics. Although several PAC1 antagonists, such as PACAP 6-38, have been reported, all of them are peptide compounds. In the present study, we identified new small-molecule antagonists of the PAC1 receptor using in silico screening and in vitro/vivo pharmacological assays. The identified small-molecule compounds, named PA-8 and PA-9, dose dependently inhibited the phosphorylation of CREB induced by PACAP in PAC1-, but not VPAC1- or VPAC2-receptor-expressing CHO cells. PA-8 and PA-9 also dose dependently inhibited PACAP-induced cAMP elevation with an IC50 of 2.0 and 5.6 nM, respectively. In vivo pharmacological assays showed that intrathecal injection of these compounds blocked the induction of PACAP-induced aversive responses and mechanical allodynia in mice. In contrast, the compounds when administered alone exerted neither agonistic nor algesic actions in the in vitro/vivo assays. The compounds identified in the present study are new and the first small-molecule antagonists of the PAC1 receptor; they may become seed compounds for developing novel analgesics.
Assuntos
Simulação por Computador , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/química , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Animais , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nociceptividade/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/uso terapêutico , Domínios Proteicos , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/química , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismoRESUMO
Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR.
Assuntos
Amidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Racemases e Epimerases/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Racemases e Epimerases/metabolismo , Relação Estrutura-AtividadeRESUMO
Aldo-keto reductase 1B10 (AKR1B10) is overexpressed in several extraintestinal cancers, particularly in non-small-cell lung cancer, where AKR1B10 is a potential diagnostic marker and therapeutic target. Selective AKR1B10 inhibitors are required because compounds should not inhibit the highly related aldose reductase that is involved in monosaccharide and prostaglandin metabolism. Currently, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (HMPC) is known to be the most potent competitive inhibitor of AKR1B10, but it is nonselective. In this study, derivatives of HMPC were synthesized by removing the 4-methoxyphenylimino moiety and replacing the benzylamide with phenylpropylamide. Among them, 4c and 4e showed higher AKR1B10 inhibitory potency (IC50 4.2 and 3.5 nM, respectively) and selectivity than HMPC. The treatments with the two compounds significantly suppressed not only migration, proliferation, and metastasis of lung cancer A549 cells but also metastatic and invasive potentials of cisplatin-resistant A549 cells.