Thiazole Derivatives Research Articles

I2/CH3ONa-Promoted Ring-Opening Alkylation of Benzothiazoles with Dialkyl Carbonates

AbstractDialkyl carbonates were used as the green alkylating reagents in the I2-promoted ring-opening alkylation of benzothiazoles. A variety of benzo[d]thiazole derivatives underwent the alkylation smoothly to provide the diverse N-alkyl-N-(o-alkylthio)phenylformamides in moderate to excellent yields. The synthetic utility of this protocol was verified by gram-scale reaction and further derivatization of the products. The mechanism of the involvement of two molecules of dialkyl carbonates in the formation of sulfur-alkyl and nitrogen-alkyl groups, respectively, was also demonstrated.

A Multicomponent Approach to Imidazo[2,1‐b]thiazole Derivatives by Sequential PdI2/KI‐Catalyzed Deprotective Oxidative Aminocarbonylation – Dearomative Cyclization – Aromatization

AbstractWe report a direct, multicomponent approach to an important class of fused‐ring heterocycles, namely, imidazo[2,1‐b]thiazole derivatives starting from simple and readily available building blocks (N‐Boc‐N‐propargylthiazol‐2‐amines, carbon monoxide, a secondary amine, and oxygen). The process takes place under the catalysis of the simple PdI2/KI system under relatively mild conditions (100 °C under 20 atm of a 4 : 1 mixture of CO‐air), and leads to 2‐(imidazo[2,1‐b]thiazol‐5‐yl)‐N,N‐dialkylacetamides in yields up to 87 %. The mechanistic pathway leading to carbonylated imidazo[2,1‐b]thiazole occurs through an ordered sequence of steps, involving amine‐induced N‐deprotection, oxidative aminocarbonylation of the triple bond (with Csp−H activation and formation of a 2‐ynamide intermediate), dearomative cyclization (by intramolecular conjugate addition of thioazolic nitrogen to the 2‐ynamide moiety) and aromatization by proton‐shift isomerization. When starting from N‐Boc‐N‐(propargyl)benzo[d]thiazol‐2‐amine, tricyclic benzimidazothiazoles were formed in moderate yields.

Pharmacological Significance of Synthetic Bioactive Thiazole Derivatives

Abstract: Thiazole and the related nuclei constitute one of the most significant moieties in the extensively emerging domain of heterocyclic compounds. The versatile nature of the thiazole nucleus can be determined as it is present in natural products like vitamin B1. Furthermore, its derivatives exhibit diverse biological activities, including antimicrobial, anticancer, antihistaminic, antioxidant, etc. They have also emerged as potent CNS agents and are primarily used in the treatment of various CNS disorders. The structure-activity relationship of various amine derivatives of ethylated thiazole demonstrates their use as potential agents in the treatment of melanoma, pigmentation as well as solar elastosis. Thiazole fused with different heterocyclic systems results in many novel derivatives with higher therapeutic activity. Benzothiazole and Thiazolopyrimidine have a distinct position in this regard. This review focuses on the central role of thiazole and its derivatives in current drug design, covering a broad spectrum of pharmacological activities associated with them.

Thiopyrano[2,3-d]thiazole structures as promising scaffold with anticancer potential

Seven chromeno[4′,3':4,5]thiopyrano[2,3-d]thiazole derivatives were synthesized and screened for their cytotoxic effects on different lines of mammalian leukemia, breast adenocarcinoma, glioblastoma, and pseudo-normal and normal cells. The derivative 3 demonstrated toxicity towards tumor cells of Jurkat, K562, U251, HL-60, MCF-7, and MDA-MB-231 lines. At the same time, this compound possessed low toxicity (IC50 > 100 μM) towards cells, used as control, representing non-tumor, somatic cells: HaCaT, HEK293 cells as well as murine Balb/c 3T3 and J774.2 cells, mink Mv1Lu cells, and normal mitogen-activated human blood lymphocytes. The derivative 3 induced apoptosis in human leukemia Jurkat T-cells and glioblastoma U251 cells via mitochondria-dependent pathway and inhibition of the DNA reparation enzyme PARP-1. This compound triggered pro-apoptotic morphological changes in Jurkat and U251 cells, namely chromatin condensation, nuclei fragmentation, and membrane blebbing. However, the DNA damaging effects of compound 3 were significantly lower in normal human lymphocytes, compared with such results in tumor Jurkat and U251 cells. The DNA damaging effects of compound 3 were unrelated to its DNA-binding and/or DNA-intercalating abilities. This compound induced the accumulation of endogenous reactive oxygen species (ROS), namely superoxide radicals, in human leukemia and glioblastoma cells. Our finding indicated that compound 3 inhibited the viability of human leukemia T-cells and glioblastoma cells via induction of DNA damage and apoptosis through ROS-mediated mitochondrial pathway.

Discovery of novel dihydropyrazole-stilbene derivatives for ameliorating heart failure through modulation of p38/NF-κB signaling pathway

Heart failure is one of the diseases with the highest mortality in the world, and inflammation is the main cause for its occurrence and development. The stilbene skeleton of resveratrol has been shown to have excellent anti-inflammatory and antioxidant activities. In order to continue our research on dihydropyrazole derivatives, a series of novel (E)-4-methyl-2-(3-phenyl-5-(4-styrylphenyl)-4,5-dihydro-1H-pyrazol-1-yl)thiazole derivatives were designed and synthesized according to the principle of molecular hybridization for evaluation their anti-inflammatory and antioxidation activities. We screened their anti-inflammatory abilities in RAW264.7 cells and analyzed the preliminary structure-activity relationship, and explored the related molecular mechanisms. We further used doxorubicin (DOX)-induced heart failure model to explore the protective role of our compound in vivo. Our results showed that compound F5 exhibited the most potent activity and was superior to the positive control. It reversed the expression of lipopolysaccharide (LPS)-regulated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and superoxide dismutase 1 (SOD1) in RAW264.7 cells. In addition, compound F5 also inhibited DOX-induced inflammation and reactive oxygen species by modulating the p38/nuclear factor kappa B (NF-κB) signaling pathway in H9C2 cells. In vivo results showed that compound F5 ameliorated DOX-caused damage, such as reduced left ventricular ejection fraction, severe inflammation, fibrosis and oxidative stress in heart. In conclusion, compound F5 could be used as a promising agent for the treatment of heart failure through attenuating oxidative stress and inflammation.

Synthesis and biological evaluation of thiazole and thiadiazole derivatives as potential anticancer agents

A new series of 4-methyl-2-{2-[(aryl)methylidene]hydrazinyl}-1,3-thiazole (2a-i), N-(4-acetyl-5-aryl)4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamides (3a-b) and N-(5-(4-(substituted phenyl)-1,3,4-thiadiazol-2-yl)acetamides (3c-i) were synthesized by the reaction of 2-((aryl)methylene)hydrazine-1-carbothioamides (1a-i) and acetic anhydride or chloroacetone. The cytotoxic activities of the products were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against Hela cervical cancer, MCF-7 breast carcinoma and HT-29 colorectal cancer cell lines. Thiazole based compounds 2a, 2b, 2f and 2i, bearing 4-bromothiophen-2-yl, naphthalen-2-yl, 2,5-difluorophenyl and 4-(trifluoromethoxy)phenyl moieties, respectively; also N-(4-acetyl-5-(naphthalen-2-yl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamide (3b) and N-(5-(2,6-difluorophenyl)-1,3,4-thiadiazol-2-yl)acetamide (3d) exhibited significant anticancer activity against three cancer cell lines. Moreover, these active compounds were further evaluated by apoptotic protein levels. The results showed that these thiazole and thiadiazole compounds induced apoptosis of cancer cells.

Synthesis and evaluation of novel xanthene-based thiazoles as potential antidiabetic agents.

A series of xanthene-based thiazoles was synthesized and characterized by different scpectroscopic methods, i.e. Proton nuclear magnetic resonance (1 H NMR), carbon nuclear magnetic resonance (13 C NMR), infrared spectroscopy, carbon hydrogen nitrogenanalysis, and X-ray crystallography. The inhibition potencies of 18 newly synthesized thiazole derivatives were investigated on the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase (α-Amy), and α-glycosidase (α-Gly) enzymes in accordance with their antidiabetic and anticholinesterase ability. The synthesized compounds have the highest inhibition potential against the enzymes at low nanomolar concentrations. Among the 18 newly synthesized molecules, 3b and 3p were superior to the known commercial inhibitors of the enzymes and have a much more effective inhibitory potential, with IC50 : 2.37 and 1.07 nM for AChE, 0.98 and 0.59 nM for BChE, 56.47 and 61.34 nM for α-Gly, and 152.48 and 124.84 nM for α-Amy, respectively. Finally, the optimized 18 compounds were subjected to molecular docking to describe the interaction between thiazole derivatives and AChE, BChE, α-Amy, and α-Gly enzymes in which important interactions were monitored with amino acid residues of each target enzyme.

Discovery of Novel N-Pyridylpyrazole Thiazole Derivatives as Insecticide Leads

To develop effective insecticides against Lepidoptera pests, 25 novel N-pyridylpyrazole derivatives containing thiazole moiety were designed and synthesized based on the intermediate derivatization method (IDM). The insecticidal activities of these target compounds against Plutella xylostella (P. xylostella), Spodoptera exigua (S. exigua), and Spodoptera frugiperda (S. frugiperda) were evaluated. Bioassays indicated that compound 7g−7j exhibited good insecticidal activities. Compound 7g showed especially excellent insecticidal activities against P. xylostella, S. exigua, and S. frugiperda with LC50 values of 5.32 mg/L, 6.75 mg/L, and 7.64 mg/L, respectively, which were adequate for that of commercial insecticide indoxacarb. A preliminary structure-activity relationship analysis showed that the insecticidal activities of thiazole amides were better than that of thiazole esters, and the amides with electron-withdrawing groups on the benzene ring were better than the ones with electron-donating groups. This work provides important information for designing novel N-pyridylpyrazole thiazole candidate compounds and suggests that the 7g is a promising insecticide lead for further studies.

Design, In-Silico Studies, Synthesis, Characterization, and Anticonvulsant Activities of Novel Thiazolidin-4-One Substituted Thiazole Derivatives

A series of novel thiazolidine-4-one substituted thiazoles were prepared using multi-step synthesis and screened for their antiepileptic potency. The chemical nature of the prepared derivatives was confirmed using FT-IR, elemental analyses, Mass spectroscopy, and 1H-NMR. Molecular properties and antiepileptic potency of the novel thiazoles were predicted using in-silico models such as molinspiration online tool and molecular docking, respectively. In-vivo antiepileptic potency of the entire title compounds was determined using MES and scPTZ method. Additionally, the rotorod test was employed to determine the neurotoxicity of the synthesized derivatives. Entire title analogs displayed -varying degrees of antiepileptic and neurotoxicity potency. The pharmacological potency of tested compounds was compared with their chemical structures. 2-(4-Nitrophenyl)-3-(4-((4-phenylthiazol-2-ylimino)methyl)phenyl) thiazolidin-4-one (PTT6) was found to be the very active derivative of this series among thirteen tested derivatives. Thus, this analog may act as a lead molecule to find potent and safer antiepileptic drugs.

Microwave-assisted synthesis of biodegradable and antibacterial thiophene, furan and thiazole derivatives

The rise of bacterial resistance to common clinical antibiotics is calling for alternative techniques to synthesize antibacterial drugs with high biodegradability. For instance, microwave-assisted synthesis is a powerful technique that accelerates organic reactions. Here, we report the synthesis of 19 thiophene derivatives, five furan derivatives, and two thiazole derivatives, using Suzuki–Miyaura cross-coupling by microwave irradiation. Compound biodegradability was measured by the closed bottle test. Results show that microwave irradiation conditions have reduced the reaction time and increased the yield, and this method uses less organic solvent compared to conventional heating. Several compounds show broad antibacterial activity. One compound showed significant antibacterial activity against Streptococcus pyogenes with a minimal inhibitory concentration of 0.097 µg/mL and against Salmonella enterica with a minimal inhibitory concentration of 0.78 µg/mL. Two furan derivatives with the best activity against pathogenic bacteria were found biodegradable and non-toxic for environmental bacteria present in wastewater treatment plants.

Synthesis and Anticancer Evaluation of New Thiazole and Thiadiazole Derivatives Bearing Acetanilide Moiety.

New thiazole and thiadiazole derivatives bound to the acetanilide moiety were synthesized and evaluated for their cytotoxic activity. The precursor N-(4-acetamidophenyl)-N'-phenylthiourea (2) was cyclocondensed with ethyl bromoacetate to afford a mixture of the two isomers, 2-(4-acetamidophenylimino)-3-phenylthiazolidin-4-one (3a, 23%) and 3-(4-acetamidophenyl)-2-phenyliminothiazolidin-4-one (3b, 71%). The Knoevenagel reaction of 3b with various aromatic aldehydes afforded 5-arylidene-2-phenyliminothiazolidin-4-one derivatives 5a-5e. Intramolecular cyclization of thiourea scaffold 2 with chloroacetone and/or phenacyl chloride gave the conforming thiazole derivatives 6a and 6b. A new series of thiadiazole derivatives 9a-9c and 11a-11c was synthesized by the reaction of N-(4-acetamidophenyl)-N'-phenylthiourea (2) with selected derivatives of hydrazonoyl halide in ethanol and triethylamine. The structures of the synthesized thiazole and thiadiazole compounds were elucidated by their compatible spectral data. The cytotoxic activity of the synthesized thiazole and thiadiazole derivatives was screened against four human cancer cell lines and showed promising results. Thiazolidin-4-one compound 5d showed the strongest cytotoxic effects on hepatocellular carcinoma (IC50 = 8.80 ± 0.31 μg/mL), mammary gland breast cancer (IC50 = 7.22 ± 0.65 μg/mL) and colorectal carcinoma (IC50 = 9.35 ± 0.61 μg/mL) cell lines.

Synthesis, molecular docking study of thiazole derivatives and exploring their dual inhibitor potentials against α-amylase and α-glucosidase

Diabetes mellitus is one of the most chronic metabolic diseases. The current study comprises of evaluation of thiazole as an antidiabetic agent. A library of sixteen derivatives was synthesized, characterized through different spectroscopic techniques, and evaluated against α-amylase and α-glucosidase enzymes. All derivatives displayed varied degree of α-amylase inhibition ranging from 0.6 ± 0.05 to 32.20 ± 0.50 µ M and α-glucosidase activity ranging from 0.50 ± 0.05 to 32.70 ± 0.50 µ M as compared to standard drug acarbose (IC 50 = 8.90 ± 0.10 µ M and 9.10 ± 0.10 µ M respectively). In both cases; derivative 6 (IC 50 = 0.6 ± 0.05 µ M & 0.50 ± 0.05 µ M) were found potent among the series. Structural activity relationship has been established for all derivatives which mainly depend upon nature, position, and number of substituent/s on the phenyl ring. A molecular docking study was carried out to find the binding interaction of the most potent derivatives with active sites of enzymes.

Synthesis and Antimicrobial Activity of New Heteroaryl(aryl) Thiazole Derivatives Molecular Docking Studies.

Herein, we report the design, synthesis, and evaluation of the antimicrobial activity of new heteroaryl (aryl) thiazole derivatives. The design was based on a molecular hybridization approach. The in vitro evaluation revealed that these compounds demonstrated moderate antibacterial activity. The best activity was achieved for compound 3, with MIC and MBC in the range of 0.23-0.7 and 0.47-0.94 mg/mL, respectively. Three compounds (2, 3, and 4) were tested against three resistant strains, namely methicillin resistant Staphylococcus aureus, P. aeruginosa, and E. coli, which showed higher potential than the reference drug ampicillin. Antifungal activity of the compounds was better with MIC and MFC in the range of 0.06-0.47 and 0.11-0.94 mg/mL, respectively. The best activity was observed for compound 9, with MIC at 0.06-0.23 mg/mL and MFC at 0.11-0.47 mg/mL. According to docking studies, the predicted inhibition of the E. coli MurB enzyme is a putative mechanism of the antibacterial activity of the compounds, while inhibition of 14a-lanosterol demethylase is probably the mechanism of their antifungal activity.

Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study.

In this study, hybrid analogs of benzimidazole containing a thiazole moiety (1–17) were afforded and then tested for their ability to inhibit α-amylase and α-glucosidase when compared to acarbose as a standard drug. The recently available analogs showed a wide variety of inhibitory potentials that ranged between 1.31 ± 0.05 and 38.60 ± 0.70 µM (against α-amylase) and between 2.71 ± 0.10 and 42.31 ± 0.70 µM (against α-glucosidase) under the positive control of acarbose (IC50 = 10.30 ± 0.20 µM against α-amylase) (IC50 = 9.80 ± 0.20 µM against α-glucosidase). A structure–activity relationship (SAR) study was carried out for all analogs based on substitution patterns around both rings B and C respectively. It was concluded from the SAR study that analogs bearing either substituent(s) of smaller size (−F and Cl) or substituent(s) capable of forming hydrogen bonding (−OH) with the catalytic residues of targeted enzymes enhanced the inhibitory potentials. Therefore, analogs 2 (bearing meta-fluoro substitution), 3 (having para-fluoro substitution) and 4 (with ortho-fluoro group) showed enhanced potency when evaluated against standard acarbose drug with IC50 values of 4.10 ± 0.10, 1.30 ± 0.05 and 1.90 ± 0.10 (against α-amylase) and 5.60 ± 0.10, 2.70 ± 0.10 and 2.90 ± 0.10 µM (against α-glucosidase), correspondingly. On the other hand, analogs bearing substituent(s) of either a bulky nature (−Br) or that are incapable of forming hydrogen bonds (−CH3) were found to lower the inhibitory potentials. In order to investigate the binding sites for synthetic analogs and how they interact with the active areas of both targeted enzymes, molecular docking studies were also conducted on the potent analogs. The results showed that these analogs adopted many important interactions with the active areas of enzymes. The precise structure of the newly synthesized compounds was confirmed using several spectroscopic techniques as NMR and HREI-MS.

New Thiazole Acetic Acid Derivatives: A Study to Screen Cardiovascular Activity Using Isolated Rat Hearts and Blood Vessels.

Cardiovascular diseases are one of the major causes of mortalities worldwide. In the present research, new synthetic derivatives of thiazole were studied using isolated hearts and blood vessels of rats. The heart and thoracic aorta were tested with six new synthesized thiazole acetic acid derivatives (SMVA-10, SMVA-35, SMVA-40, SMVA-41, SMVA-42 and SMVA-60), and the data obtained were statistically analyzed and compared. Isolated rat hearts were used to record the changes in developed tension and heart rate, while thoracic aortas were used to measure the contractile response, before and after treatments. Analysis of the results indicated a significant (p < 0.01) increase in developed tension with the addition of SMVA-35, SMVA-40, SMVA-41 and SMVA-42, which was augmented in the presence of adrenaline without affecting the heart rate. On the other hand, acetylcholine significantly decreased the developed tension, which was significantly reversed (p < 0.01) in the presence of compounds (SMVA-35 and SMVA-60). However, in the presence of SMVA-35 and SMVA-40, acetylcholine-induced bradycardia was significantly (p < 0.01) reduced. Furthermore, only SMVA-42 induced a dose-dependent contractile response in the isolated blood vessel, which was abolished in the presence of prazosin. Therefore, it can be concluded that some of the new synthesized thiazole derivatives exhibited promising results by raising the developed tension without changing the heart rate or blood vessel function, which could be helpful in failing heart conditions. However, more research is required to fully comprehend the function, mechanism and effectiveness of the compounds.

Multipotent Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease: Synthesis, Biological Analysis and Molecular Docking Study of Benzimidazole-Based Thiazole Derivatives.

Twenty-four analogues of benzimidazole-based thiazoles (1–24) were synthesized and assessed for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory potential. All analogues were found to exhibit good inhibitory potential against cholinesterase enzymes, having IC50 values in the ranges of 0.10 ± 0.05 to 11.10 ± 0.30 µM (for AChE) and 0.20 ± 0.050 µM to 14.20 ± 0.10 µM (for BuChE) as compared to the standard drug Donepezil (IC50 = 2.16 ± 0.12 and 4.5 ± 0.11 µM, respectively). Among the series, analogues 16 and 21 were found to be the most potent inhibitors of AChE and BuChE enzymes. The number (s), types, electron-donating or -withdrawing effects and position of the substituent(s) on the both phenyl rings B & C were the primary determinants of the structure-activity relationship (SAR). In order to understand how the most active derivatives interact with the amino acids in the active site of the enzyme, molecular docking studies were conducted. The results obtained supported the experimental data. Additionally, the structures of all newly synthesized compounds were elucidated by using several spectroscopic methods like 13C-NMR, 1H-NMR and HR EIMS.

Design, Synthesis, and biological evaluation of a novel series of thiazole derivatives based on pyrazoline as anticancer agents

Design, Synthesis, and biological evaluation of a novel series of thiazole derivatives based on pyrazoline as anticancer agents

Aggregation induced emission and mechanofluorochromism of tetraphenylethene fused thiazolo[5,4‑d]thiazole derivatives

We designed and prepared novel MFC materials (TPE-B, TPE-T) with D-π-A scaffolds containing thiazolo[5,4-d]thiazole and TPE units. The results proved that TPE-B and TPE-T exhibited obvious AIE properties and reversible MFC behavior. The performance in solid state of TPE-B and TPE-T presented that the mechanical force led to 25–28 nm red-shift, and could recover to the original state by solvent soaking. The powder XRD reveal that the morphological change from crystalline to amorphous state could be responsible for mechanochromism. Moreover, TPE-B and TPE-T could be constructed the rewritable information storage systems. This research work provides valuable reference for the design of MCF materials.

Synthesis and Molecular Docking Study of New Thiazole Derivatives as Potential Tubulin Polymerization Inhibitors.

A new series of 2,4-disubstituted thiazole derivatives containing 4-(3,4,5-trimethoxyphenyl) moiety was synthesized and evaluated for their potential anticancer activity as tubulin polymerization inhibitors. All designed compounds were screened for cytotoxic activity against four human cancer cell lines, namely, HepG2, MCF-7, HCT116, and HeLa, using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, with combretastatin A-4 as a reference drug. Compounds 5c, 6d, 7c, 8, and 9a,b showed superior activity against the tested cell lines, with IC50 values ranging from 3.35 ± 0.2 to 18.69 ± 0.9 μM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their antiproliferative activity. The obtained results suggested that compounds 5c, 7c, and 9a remarkably inhibit tubulin polymerization, with IC50 values of 2.95 ± 0.18, 2.00 ± 0.12, and 2.38 ± 0.14 μM, respectively, which exceeded that of the reference drug combretastatin A-4 (IC50 2.96 ± 0.18 μM). Molecular docking studies were also conducted to investigate the possible binding interactions between the targeted compounds and the tubulin active site. The interpretation of the results showed clearly that compounds 7c and 9a were identified as the most potent tubulin polymerization inhibitors with promising cytotoxic activity and excellent binding mode in the docking study.

Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors

Aiming to develop novel tropomyosin receptor kinase A (TrkA) inhibitors, a scaffold hopping strategy was utilized by transforming the fused indazole of Entrectinib to phenyl triazole/thiazole skeleton to obtain compounds 7a-7 h and 13a-13 h. In the light of MTT assay, phenyl triazole derivatives 7a-7 h exhibited moderate anti-proliferative activities against KM-12 cells with the IC50 values of 1.78–17.51 μM, while phenyl thiazole derivatives 13a-13 h showed the weaker efficacy. Further structure-guided optimizations by combining the phenyl triazole skeleton with 3,5‑difluorophenyl and 3-carbamoyl-4-piperazinylaniline moiety led to compounds 19a-19d and 20. Eventually, 19c bearing (2-(4-methylpiperazin-1-yl)phenyl)(morpholino)methanone moiety exhibited excellent anti-proliferative activity on TrkA-positive KM-12 cells with IC50 value of 0.17 μM. Meanwhile, compound 19c showed the inhibitory potency on TrkA with IC50 value of 1.6 nM, and displayed higher selectivity on TrkA over TrkB (IC50 = 12.3 nM) and TrkC (IC50 = 18.4 nM). The dedicated wound healing and colony formation assay indicated that the optimal compound 19c could suppress migration and significantly inhibit KM-12 cell colony formation in a dose-dependent manner. In addition, 19c could weakly induce apoptosis of KM-12 cell in immunofluorescent staining analysis. Taken together, the above results suggest 19c as a novel TrkA inhibitor worthy of further profiling.