Compounds 4h Research Articles

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein complex (GPC) are promising inhibitors of LASV. In this study, we synthesized two series of LASV inhibitors based on the benzimidazole structure. Lentiviral pseudotypes bearing the LASV GPC were established to identify virus entry inhibitors. Surface plasmon resonance (SPR) was further used to verify the binding activities of the potential compounds. Compounds 7d-Z, 7h-Z, 13c, 13d, and 13f showed relatively excellent antiviral activities with IC50 values ranging from 7.58 to 15.46 nM and their SI values above 1251. These five representative compounds exhibited stronger binding affinity with low equilibrium dissociation constants (KD < 8.25 × 10-7 M) in SPR study. The compound 7h-Z displayed the most potent antiviral activity (IC50 = 7.58 nM) with a relatively high SI value (2496), which could be further studied as a lead compound. The structure-activity relationship indicated that the compounds with lipophilic and spatially larger substituents might possess higher antiviral activity and a much larger safety margin. This study will provide some good guidance for the development of highly active compounds with a novel skeleton against LASV.

Fluorinated benzimidazolium salts: Synthesis, characterization, molecular docking studies and inhibitory properties against some metabolic enzymes

Here, a number of symmetric and unsymmetric N-heterocyclic carbene (NHC) precursors based on benzimidazol-2-ylidene are synthesized. The N-benzyl substituent in these compounds has an electron-withdrawing group (F) at the para position. The structure of these compounds was characterized using elemental analysis and various spectroscopic methods (FTIR and NMR). The molecular and crystal structures of compound 1f and compound 1h were unambiguously elucidated through single-crystal X-ray diffraction analysis. According to the X-ray studies, compound 1f exhibits the formation of a U-shaped molecule whereas compound 1h has a Z-shape formation. In addition, the enzyme inhibition activities of these compounds were investigated against acetylcholinesterase (AChE) and carbonic anhydrases (hCAs). They showed a highly potent inhibition effect on AChE and hCAs (Ki values are in the range of 14.84±1.91 to 174.80±23.60 nM for AChE, 22.41±1.93 to 188.67±27.05 nM for hCA I and 35.29±7.21 to 136.55±17.61 nM for hCA II). These results may contribute to the design and development of new drug candidates, particularly for treatment of some widespread disorders displayed in the world including Alzheimer's disease and glaucoma.

2-Phenylpyridine Derivatives: Synthesis and Insecticidal Activity against Mythimna separata, Aphis craccivora, and Tetranychus cinnabarinus

The increase in the insecticide resistance of pests, such as Mythimna separata, Aphis craccivora Koch, and Tetranychus cinnabarinus, necessitates the development of new heterocyclic compounds with high insecticidal activity. A series of novel 2-phenylpyridine derivatives containing N-phenylbenzamide moieties were designed and synthesised with Suzuki-Miyaura cross-coupling, nucleophilic substitution, and amidation reactions. The reaction conditions in each step are mild, and the product is easy to separate (yield is about 85%). The structures of the compounds were characterised using 1H and 13C NMR spectroscopy and HRMS. Moreover, the insecticidal activity of the compounds was analysed using the leaf dipping method. The compounds 5a, 5d, 5g, 5h, and 5k at 500 mg/L exhibited 100% inhibition against Mythimna separata. Therefore, the 2-phenylpyridine moieties have the potential to lead to the discovery of novel and effective insecticides.

Discovery of novel 2-(4-(benzyloxy)-5-(hydroxyl) phenyl) benzothiazole derivatives as multifunctional MAO-B inhibitors for the treatment of Parkinson’s disease

To discover novel multifunctional agents for the treatment of Parkinson’s disease, a series of 2-(4-(benzyloxy)-5-(hydroxyl) phenyl) benzothiazole derivatives was designed, synthesized and evaluated. The results revealed that representative compound 3h possessed potent and selective MAO-B inhibitory activity (IC50 = 0.062 µM), and its inhibitory mode was competitive and reversible. Additionally, 3h also displayed excellent anti-oxidative effect (ORAC = 2.27 Trolox equivalent), significant metal chelating ability and appropriate BBB permeability. Moreover, 3h exhibited good neuroprotective effect and anti-neuroinflammtory ability. These results indicated that compound 3h was a promising candidate for further development against PD.

Discovery of New Boswellic Acid Hybrid 1H-1,2,3-Triazoles for Diabetic Management: In Vitro and In Silico Studies.

A series of 24 new 1H-1,2,3-triazole hybrids of 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA (1)) and 11-keto-β-boswellic acid (β-KBA (2)) was designed and synthesized by employing "click" chemistry in a highly efficient manner. The 1,3-dipolar cycloaddition reaction between β-AKBA-propargyl ester intermediate 3 or β-KBA-propargyl ester intermediate 4 with substituted aromatic azides 5a-5k in the presence of copper iodide (CuI) and Hünig's base furnished the desired products-1H-1,2,3-triazole hybrids of β-AKBA (6a-6k) and β-KBA (7a-7k)-in high yields. All new synthesized compounds were characterized by 1H-, 13C-NMR spectroscopy, and HR-ESI-MS spectrometry. Furthermore, their α-glucosidase-inhibitory activity was evaluated in vitro. Interestingly, the results obtained from the α-glucosidase-inhibitory assay revealed that all the synthesized derivatives are highly potent inhibitors, with IC50 values ranging from 0.22 to 5.32 µM. Among all the compounds, 6f, 7h, 6j, 6h, 6g, 6c, 6k, 7g, and 7k exhibited exceptional inhibitory potency and were found to be several times more potent than the parent compounds 1 and 2, as well as standard acarbose. Kinetic studies of compounds 6g and 7h exhibited competitive and mixed types of inhibition, with ki values of 0.84 ± 0.007 and 1.18 ± 0.0012 µM, respectively. Molecular docking was carried out to investigate the binding modes of these compounds with α-glucosidase. The molecular docking interactions indicated that that all compounds are well fitted in the active site of α-glucosidase, where His280, Gln279, Asp215, His351, Arg442, and Arg315 mainly stabilize the binding of these compounds. The current study demonstrates the usefulness of incorporating a 1H-1,2,3-triazole moiety into the medicinally fascinating boswellic acids skeleton.

Exploring novel fluorine-rich fuberidazole derivatives as hypoxic cancer inhibitors: Design, synthesis, pharmacokinetics, molecular docking, and DFT evaluations.

Sixteen fuberidazole derivatives as potential new anticancer bioreductive prodrugs were prepared and characterized. The in vitro anticancer potential was examined to explore their cytotoxic properties by employing apoptosis, DNA damage, and proliferation tests on chosen hypoxic cancer cells. Eight substances (Compound 5a, 5c, 5d, 5e, 5g, 5h, 5i, and 5m) showed promising cytotoxicity values compared to the standard control. The potential of compounds was also examined through in silico studies (against human serum albumin), including chem-informatics, to understand the structure-activity relationship (SAR), pharmacochemical strength, and the mode of interactions responsible for their action. The DFT calculations revealed that only the 5b compound showed the lowest ΔET (2.29 eV) while 5i showed relatively highest βtot (69.89 x 10-31 esu), highest αave (3.18 x 10-23 esu), and dipole moment (6.49 Debye). This study presents a novel class of fuberidazole derivatives with selectivity toward hypoxic cancer cells.

Novel heterocyclic analogues of bergenin as anti-mitotic agents: Design, synthesis, biological evaluation and molecular docking study

In continuation of our effortsin the development of natural product-based tubulin inhibitors with potential anti-mitotic activities, a novel bergenin hybrids incorporating sulfonate and 1, 2, 3-triazole moieties at carbon-11 were designed and synthesized. The in vitro cytotoxic activity of these derivatives (3a-i, 6a-k and 7a-g) was assessed against various cancer cells and majority of derivatives in this study were shown potent anticancer activity against tested cancer cells than that parent compound. Especially, the compounds 3i, 6g, and 6h exhibited significant activity against HeLa cell line with IC50 of 9.1 ± 0.4, 10 ± 0.2, and 7 ± 0.1 µM, which is comparable to the standard drug, nocodazole (IC50 5.2 ± 1.3 µM). The flowcytometry analysis indicated that the compounds 3i, 6g, and 6h arrest cells at G2/M phase and increased expression of mitotic markers, Cyclin B1 and PLK1 proteins. In addition, 3i, 6g, and 6h generate the oxidative stress and induce apoptosis in the HeLa cells was confirmed with flowcytometry analysis. Molecular docking studies revealed that the compounds 3i, 6g, and 6h have significant binding energy with PLK1 and Cyclin B1 protein and regulating the apoptotic process.

Synthesis, antimicrobial activity and molecular docking studies of spiroquinoline-indoline-dione and spiropyrazolo-indoline-dione derivatives

Spiro[benzo[h]quinoline-7,3′-indoline]diones and spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]diones were efficiently synthesized via one-pot multi-component reactions under ultrasound-promoted conditions. Spiro[benzo[h]quinoline-7,3′-indoline]dione derivatives were successfully developed by the reaction of isatins, naphthalene-1-amine and 1,3-dicarbonyl compounds. The spiro[indoline-3,4′-pyrazolo[3,4-b]quinoline]dione derivatives were prepared by the reaction of isatins, 5-amino-1-methyl-3-pheylpyrazole, and 1,3-dicarbonyl compounds by using ( ±)-camphor-10-sulfonic acid as a catalyst in H2O/EtOH (3:1 v/v) solvent mixture. The antibacterial activity of the synthesized compounds was evaluated against, Enterococcus faecalis, Staphylococcus aureus and Candida albicans. Compounds 4b, 4h, and 6h showed the strongest antimicrobial activity toward both bacteria. The MIC values of these compounds ranged from 375–3000 µg/mL. The effect of these compounds (4b, 4h, 6h) as a function of applied dose and time was investigated by a kinetic study, and the interaction with these antimicrobial results was simulated by a molecular docking study. We also used the docking approach with Covid-19 since secondary bacterial infections. Docking showed that indoline-quinoline hybrid compounds 4b and 4h exerted the strongest docking binding value against the active sites of 6LU7. In addition, the synthesized compounds had a moderate to good free radical scavenging activity.

Synthesis and Biological Evaluation of Novel N-[3-fluoro-4-(morpholin-4-yl)phenyl]thiazol-2-amine Derivatives as Potent Antibacterial and Anticancer Agents and ADMET

In search of better antibacterial and anticancer agents, this report presents a series of novel N-[3-fluoro-4-(morpholin-4-yl)aryl]thiazol-2-amine derivatives (6a–6l) that were synthesized and evaluated for their antibacterial and anticancer activity in vitro. Antibacterial activity against three G+ bacterial strains and anticancer activity against MCF-7 and A-549 was evaluated. Among all the tested compounds, 6i and 6j exhibited potent antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis bacterial strains. Biofilm profiles for the potent compounds and it was observed from the results that the active derivatives 6i and 6j were not only potent antibacterial agents but also efficient inhibitors of S. aureus and S. epidermidis biofilm growth. Compared to the standard drug, erlotinib, the anticancer activity screening results of 6h and 6k demonstrated high cytotoxic activity against the A-549 cancer cell line. Later, the results of the inhibitory assay of potent compounds 6h and 6k against the tyrosine kinase EGFR revealed that compound 6k showed ≈1.5 fold potency of the reference drug erlotinib. Finally, compounds 6h, 6i, 6j, and 6k did not show AMES toxicity and followed the rules of Lipinski, Ghose, Veber, Egan, and Muegge rules without any deviation.

Discovery of novel 2-hydroxyl-4-benzyloxybenzyl aniline derivatives as potential multifunctional agents for the treatment of Parkinson's disease

To discover novel multifunctional agents for the treatment of Parkinson's disease, a series of 2-hydroxyl-4-benzyloxybenzyl aniline derivatives was designed, synthesized and evaluated. The biological screening indicated that representative compound 6h possessed excellent MAO-B inhibition (IC50 = 0.014 μM), high antioxidant activity (ORAC = 2.14 Trolox equivalent), good metal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Additionally, 6h exhibited great ability to alleviate the neuroinflammtion by suppressing the activation of NF-κB pathway in vitro. Furthermore, 6h can also ameliorate MPTP induced Parkinson's disease symptoms in mice by improving the dopamine level and repressing oxidative damage. These results indicated that compound 6h was a promising candidate for further development against PD.

Synthesis and Development of N-2,5-Dimethylphenylthioureido Acid Derivatives as Scaffolds for New Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens

The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation of novel thiazole derivatives using representative Gram-negative and Gram-positive strains, including tedizolid/linezolid-resistant S. aureus, as well as emerging fungal pathogens. The 4-substituted thiazoles 3h, and 3j with naphthoquinone-fused thiazole derivative 7 with excellent activity against methicillin and tedizolid/linezolid-resistant S. aureus. Moreover, compounds 3h, 3j and 7 showed favourable activity against vancomycin-resistant E. faecium. Compounds 9f and 14f showed broad-spectrum antifungal activity against drug-resistant Candida strains, while ester 8f showed good activity against Candida auris which was greater than fluconazole. Collectively, these data demonstrate that N-2,5-dimethylphenylthioureido acid derivatives could be further explored as novel scaffolds for the development of antimicrobial candidates targeting Gram-positive bacteria and drug-resistant pathogenic fungi.

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

Discovery of aromatic 2-(3-(methylcarbamoyl) guanidino)-N-aylacetamides as highly potent chitinase inhibitors

Chitinases are important glycoside hydrolases that are closely related to bacterial pathogenesis, fungal cell wall remodelling, and insect moulting. Consequently, chitinases have become attractive targets for therapeutic drugs and pesticides. In this study, we designed and synthesised a series of novel chitinase inhibitors based on the N-methylcarbamoylguanidinyl group of the natural product argifin. The most active compound 8h showed strong inhibitory activity against the group I chitinases HsChit1, SmChiB, and OfChi-h, with IC50 values of 0.19 µM, 4.2 nM, and 25 nM, respectively. Binding mode studies revealed that the compound 8h formed π-π stacking/hydrophobic interactions at +1 or +2 subsite of chitinases. In addition, a key hydrogen bond net was formed between the pharmacophore N-methylcarbamoylguanidinyl and key residues at the −1 subsite. Together, the findings of this study provide novel insights into the development of potent small-molecule chitinase inhibitors using a combination of planar structures and N-methylcarbamoylguanidinyl.

Design, synthesis, molecular docking, and biological evaluation of coumarin-thymidine analogs as potent anti-TB agents.

With the intent to discover new antituberculosis (TB) compounds, coumarin-thymidine analogs were synthesized using second-order nucleophilic substitution reactions of bromomethyl coumarin with thymidine. The newly synthesized coumarin-thymidine conjugates (1a-l) were characterized using IR, NMR, GC-MS, and CHN elemental analysis. The novel conjugates were found to exhibit potent anti-TB activity against the Mycobacterium tuberculosis H37 Rv strain, with minimum inhibitory concentrations (MIC) of the active compounds ranging between 0.012 and 0.482 µM. Compound 1k was established as the most active candidate with a MIC of 0.012 µM. The toxicity study on HEK cells confirmed the nontoxic nature of compounds 1e, 1h, 1i, 1j, and 1k. Also, the most active compounds (1k, 1j, and 1e) were stable in the pH range from 2.5 to 10, indicating compatibility with the biophysical environment. Based on the pKa studies, compounds 1k, 1j, and 1e are capable of crossing lipid-membrane barriers and acting on target cells. Molecular docking studies on the M. tuberculosis β-oxidation trifunctional enzyme (PDB ID: 7O4V) were conducted to investigate the mechanisms of anti-TB activity. All compounds showed excellent hydrogen binding interactions and exceptional docking scores against M. tuberculosis, which was in accordance with the results. Compounds 1a-l possessed excellent affinity to proteins, with binding energies ranging from -7.4 to -8.7 kcal/mol.

Computational Design of Azine-Linked Hybrids of 2-Indolinone-Thiazolodine Scaffold as Novel and Promising Quorum Sensing Inhibitors

Microbial multidrug resistance is becoming a global menace to humanity, and finding alternative approaches to combat these “superbugs” is critical. Targeting quorum sensing (QS), which is essential for bacterial biofilm formation and virulence factors production, represents a viable alternative strategy for combating a variety of diseases. Accordingly, the current work reports potential QS inhibitors (QSIs), which could target the transcriptional regulator protein CviR in the model QS bacterium Chromobacterium violaceum. A set of novel hybrids 4(a–k) were synthesized using the virtual screening results of structurally based hybrids of the 2-indolinone-thiazolidine scaffold on the CviR active pocket residues. The ability of these hybrids to inhibit the QS system was tested against C. violaceum, and two molecules (4h and 4i) revealed promising antivirulence activity. Biofilm formation and motility were both impaired in the treated bacterial cells. Moreover, the molecular docking of these two compounds was comparable with that of chlorolactone (CL), a native inhibitor of the C. violaceum CviR. The global chemical descriptors were calculated for compounds 4h and 4i and found to be more reactive than the native inhibitor, CL. Furthermore, the in silico ADME prediction profiles of these two lead compounds, 4h and 4i, showed good ADME profiles.

Novel 4-arylaminoquinazoline derivatives: design, synthesis, crystal structure and biological evaluation as potent antitumor agents

A series of novel 4-arylaminoquinazoline derivatives were designed and synthesized. All target compounds synthesized were characterized and confirmed by 1H NMR and IR. The crystal structures of compounds 4a and 4h were prepared by the natural solvent evaporation method, and the crystal data were collected by X-ray single crystal diffractometer. The crystal data of 4a are: C19H19N3O3, M = 337.37, monoclinic, a = 10.1213(4) Å, b = 16.0054(6) Å, and c = 10.5629(4) Å. The crystal data of 4h are: C21H22N4O4, M = 394.42, monoclinic, a = 13.2448(6) Å, b = 16.3553(7) Å, and c = 9.0453(5) Å. In addition, IC50 values of all synthesized derivatives were evaluated against MKN45 cell lines. Most of the synthetic derivatives had moderate to good antiproliferative activity against the MKN45 tumor cell line. The IC50 value of compound 4a against MKN45 cell line was 2.5 μM and the inhibitory activity was higher than that of the positive control Gefitinib (IC50 = 3.2 μM), showing the better antitumor activity. Molecular docking further revealed that the better inhibitory activity of compound 4a was obtained due to the hydrogen bonding between 4a and EGFR. Moreover, AO/EB staining results showed that compound 4a could induce apoptosis of human lung cancer A549 cells. More importantly, ADME data exhibited the new compounds were all readily absorbed and had good drug-likeness. Therefore, these compounds offer the possibility to develop novel antitumor drugs.

HFIP-mediated multicomponent reactions for the synthesis of fluorescent quinoline-fused pyrroles

Herein we report a metal-free multicomponent reaction for the synthesis of diverse quinoline-fused pyrroles using 1,1,1,3,3,3-hexafluoro isopropanol (HFIP) as a reaction medium cum promoter. The reaction of aryl glyoxals, 4-hydroxycoumarin or other cyclic 1,3-dicarbonyl compounds, and 6/5-aminoquinoline or 5-aminoisoquinoline in the HFIP medium under reflux conditions provide regioselective corresponding quinoline/isoquinoline-fused pyrroles. This methodology is applicable to a wide range of substrates and provided quinoline/isoquinoline-fused pyrroles in good to very good yields. The notable features of this protocol are metal-free conditions, operational simplicity, easy purification, and the presence of bioactive pyrrole, quinoline/isoquinoline and cyclic 1,3-dicarbonyl moieties in the products. Most of the synthesized fused pyrroles exhibit fluorescence properties. The photophysical properties of all the synthesized fused pyrroles were studied by recording UV–Visible and steady-state fluorescence spectroscopy. Compounds 4a, 4e, 4f, 4h, 4i and 4s showed very good fluorescence quantum yields.

Synthesis of novel thiazoles bearing lupeol derivatives as potent anticancer and anti-inflammatory agents

Lupeol is one of the most important metabolite in the class of terpenoids and possess excellent anticancer, anti-inflammatory, anti-diabetic activities etc. In the present study, the different thiazoles and oxazoles bearing lupeol derivatives were prepared to enhance their biological activity. Initially, the in vitro cytotoxic activity results showed that the synthesized lupeol derivatives (9a–9j and 10a–10e) showed significant activity against various cancer cells and the compounds 9h and 10b exhibited excellent activity against CAL27 cells. Further, these compounds 9h and 10b arrest the cell cycle at S phase and induce the late apoptosis in CAL27 cells by downregulating the BcL2 and vimentin expression and upregulating the Bax gene expression. Moreover, the lupeol derivatives showed dose-dependent anti-inflammatory activity by inhibiting the secretion of IL-6 cytokines in LPS-induced Raw 264.7 cells. Together, these results clearly indicated that the thiazoles and oxazoles bearing lupeol derivatives can used as chemotherapeutic drugs against cancer and inflammatory diseases.

Synthesis of novel pyrazolic analogues of chalcones as potential antibacterial and antifungal agents

The present includes the synthesis of pyrazoline derivatives using chalcones and phenyl hydrazine in the presence of ethanol. It also reveals that 2-pyrazoline complexes are physiologically active and may be used in a variety of therapeutic functions. FT-IR, 1H-NMR, 13C-NMR, LC-MS, and elemental analyses were used to characterise newly synthesised phenyl-pyrazoline derivatives. The antimicrobial activity of the synthesised compounds was assessed using the agar well diffusion assay and the Minimum Inhibition Concentration (MIC). Compounds 4b, 4f, and 4h have exhibited remarkable antibiotic action against bacterial strains such as Staphylococcus aureus, Bacillus subtilis, Salmonella. Typhi, and Shigella sp. On the other hand, compound 4h had significant antifungal activity against Candida albicans and Aspergillus fusarium and was a highly promising agent when compared to standard nystatin.

Design, synthesis, and biological evaluation of novel pyrimidin-2-amine derivatives as potent PLK4 inhibitors.

Serine/threonine protein kinase PLK4 is a master regulator of centriole duplication, which is significant for maintaining genome integrity. Accordingly, due to the detection of PLK4 overexpression in a variety of cancers, PLK4 has been identified as a candidate anticancer target. Thus, it is a very meaningful to find effective and safe PLK4 inhibitors for the treatment of cancer. However, the reported PLK4 inhibitors are scarce and have potential safety issues. In this study, a series of novel and potent PLK4 inhibitors with an aminopyrimidine core was obtained utilizing the scaffold hopping strategy. The in vitro enzyme activity results showed that compound 8h (PLK4 IC50 = 0.0067 μM) displayed high PLK4 inhibitory activity. In addition, compound 8h exhibited a good plasma stability (t1/2 > 289.1 min), liver microsomal stability (t1/2 > 145 min), and low risk of DDIs. At the cellular level, it presented excellent antiproliferative activity against breast cancer cells. Taken together, these results suggest that compound 8h has potential value in the further research of PLK4-targeted anticancer drugs.