Compounds 4m Research Articles

Antiamoebic Activity of Imidazothiazole Derivatives against Opportunistic Pathogen Acanthamoeba castellanii.

We examined the antiamoebic effect of several imidazothiazole derivatives on Acanthamoeba castellanii of the T4 genotype. Trypan blue exclusion assays and haemocytometer counting were used to determine the reduction in A. castellanii trophozoite proliferation, in response to treatment with these compounds. To determine the effects of these compounds on host cells, lactate dehydrogenase assay was performed using HeLa cell lines. Amoebicidal assays revealed that the tested compounds at concentrations of 50 µM significantly inhibited amoebae trophozoites compared to controls. Compounds 1m and 1zb showed the highest amoebicidal effects eradicating 70% and 67% of A. castellanii, respectively. The compounds blocked both the encystation and excystation process in A. castellanii. Compounds 1m and 1zb blocked 61% and 55%, respectively, of amoeba binding to human cells. Moreover, the compounds showed minimal cytotoxic effects against host cells and considerably reduced amoeba-mediated host cell death. Overall, our study revealed that compounds 1m and 1zb have excellent antiamoebic potential, and should be considered in the development of curative antiamoebic medications in future studies. Further work is critical to determine the translational value of these findings.

Synthesis of Hinokitiol Sulfonate Derivatives and Their Anti-Oomycete and Nematicidal Activities.

In order to explore novel natural product-based anti-oomycete and nematicidal agents, sixteen unreported 2-sulfonyloxyhinokitiol derivatives were prepared using the principle of active splicing, and structurally confirmed by proton nuclear magnetic resonance (1 H-NMR), carbon-13 nuclear magnetic resonance (13 C-NMR), high-resolution mass spectrometry (HRMS), and melting point. Moreover, we evaluated the title compounds as anti-oomycete and nematicidal agents against two serious agricultural pests of Phytophthora capsici and Meloidogyne incongnita. Among the sixteen hinokitiol esters tested: (1) Compounds 3a and 3m exhibited the most potent anti-oomycete activity compared to zoxamide against P. capsici, and the median effective concentration (EC50 ) values of 3a, 3m, and zoxamide were 18.64, 21.11, and 23.15 mg/L, respectively; Further studies showed that the existence of seven membered ring and carbonyl group was the necessary condition for the high anti-oomycete activity of hinokitiol. (2) Compounds 3n and 3p exhibited more promising nematicidal activity than hinokitiol, and the median lethal concentration (LC50 ) values of 3n, 3p and 1 against M. incongnita were 0.2111, 0.2079, and 0.3933 mg/L, respectively. This result will pave the way for further modification of hinokitiol to develop potential new fungicides and nematicides.

Enaminone-based carboxylic acids as novel non-classical carbonic anhydrases inhibitors: design, synthesis and in vitro biological assessment

In searching for new molecular drug targets, Carbonic Anhydrases (CAs) have emerged as valuable targets in diverse diseases. CAs play critical functions in maintaining pH and CO2 homeostasis, metabolic pathways, and much more. So, it is becoming attractive for medicinal chemists to design novel inhibitors for this class of enzymes with improved potency and selectivity towards the different isoforms. In the present study, three sets of carboxylic acid derivatives 5a–q, 7a–b and 12a–c were designed, developed and evaluated for the hCA inhibitory effects against hCA I, II, IX and XII. Compounds 5l, 5m, and 5q elicited the highest inhibitory activities against hCA II, IX and XII. In summary, structural rigidification, regioisomerism and structural extension, all played obvious roles in the degree of hCA inhibition. This present work could be a good starting point for the design of more non-classical selective hCA inhibitors as potential targets for several diseases.

Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity.

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms.

Development of spiro-3-indolin-2-one containing compounds of antiproliferative and anti-SARS-CoV-2 properties

A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2′-pyrrolidine-3′,3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Anticancer and antimicrobial activities of Imine containing compounds

A series of imine derivatives (3a-m) including thio-semicarbazone, semicarbazone, thiazole and oxazole functional moieties were examined for anti-cancer activity in-vitro by MTT assay using glioblastoma cell line (U87). Among all compound 3m was most potent compound with IC50 value of 8.86 ± 0.15 µM. Cytotoxicity of compounds were evaluated using normal human embryonic kidney cell line i.e HEK-293. Moreover, antibacterial activity of synthesized derivatives was also evaluated by disc diffusion method.

Synthesis, molecular docking and enzyme inhibitory approaches of some new chalcones engrafted pyrazole as potential antialzheimer, antidiabetic and antioxidant agents

About 25 chalcones engrafted pyrazole scaffold combined with benzothiophene and indole moieties 5a-y were designed and constructed in two steps using readily available acetyl acetone, phenyl hydrazine and DMF-DMA as starting material. The synthesized chalcone analogs were screened for in vitro anti-acetylcholinesterase potential, antidiabetic potential against α-glucosidase and α-amylase, and antioxidant potentials against DPPH free radicals. The compounds 5a, 5r, 5m, 5o and 5p showed strongest acetylcholine esterase inhibition (AChEI) with IC50 values of 5 ± 1.16 μg/mL (5p), 8 ± 0.14 μg/mL (5a), 8 ± 0.57 μg/mL (5r), 10 ± 1.73 μg/mL (5m) and 10 ± 0.60 μg/mL (5o). The highest inhibition against α-glucosidase was demonstrated by compounds 5f, 5o, 5j, 5e, 5c, and 5a with IC50 values of 4 ± 0.14, 6 ± 0.43, 8 ± 0.43, 10 ± 0.11, 11 ± 0.28 and 12 ± 0.57 μg/mL respectively, whereas, the compounds 5x, 5d, 5w, 5y and 5u showed prominent α-amylase inhibition with IC50 values of 20 ± 1.15 μg/mL (5x), 30 ± 0.60 μg/mL (5d), 40 ± 0.72 μg/mL (5w), 40 ± 0.50 μg/mL (5y), and 60 ± 2.19 μg/mL (5u). The highest anti-oxidant potential against DPPH free radicals was demonstrated by compounds 5w, 5v and 5y with IC50 values of 160 ± 5.77, 260 ± 4.63, and 360 ± 4.04 μg/mL respectively. Molecular docking was used to study their interaction with the active site of enzymes.

Novel difluoromethylated 1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6 receptor antagonist with AMDE-improving properties: Design, synthesis, and biological evaluation

Serotonin type 6 receptor (5-HT6R) has been considered as a particularly promising target for treating cognitive deficits due to the positive effects of its antagonists in a wide range of memory impairment paradigms. In this study, we designed, synthesized, and evaluated a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6R antagonists. Structure-activity relationship study led to the discovery of five compounds (6a, 6m, 6n, 6p and 6q) with potent binding affinity at 5-HT6R. In in vivo pharmacokinetic studies in rats, 6p showed 30-folds higher AUC (267 ng·h/mL) and better bioavailability (34.39 %) than those of 6a (9.37 ng·h/mL and 5.95 %, respectively) by using difluoromethyl group replacing a methyl group. Besides, 6p showed good brain penetration with Cb/Cp ratio ∼6. Based on the pharmacological characteristics and favorable pharmacokinetic properties, 6p was further chosen to evaluate cognition-enhancing property in the preliminary in vivo models. It is identified that 6p not only prevented scopolamine-induced learning deficits in the novel object recognition test but also rescued the recognition barrier caused by scopolamine. Finally, the combination of 6p and donepezil produces synergistic effects on increasing the acetylcholine levels in the intracerebral hippocampus. In light of these findings, we propose 6p as a potential 5-HT6R antagonist for treatment of AD.

Synthesis and evaluation of hydrazinyl-containing pyrrolo[2,3-d]pyrimidine series as potent, selective and oral JAK1 inhibitors for the treatment of rheumatoid arthritis

Selective inhibition of JAK kinases within the JAK family has been a desired goal of research in order to maximize efficacy while reducing undesired off target effect. Aiming to minimize adverse effects such as anemia, a promising new class of pyrrolo[2,3-d]pyrimidine series containing a hydrazinyl moiety were synthesized and profiled. Among them compound 8m and 8o showed the best enzymatic activity against JAK1 with IC50 value of 0.16 nM and 0.3 nM respectively, and with selectivity over JAK2 by 40.6 and 10 folds respectively. In addition, 8o had an improved PK profile and demonstrated better in vivo efficacy than Tofacitinib in CIA model.

L-proline catalyzed ring transformation of 5-substituted tetrazole to 1,3,4-oxadiazoles as anti-tubercular agents

An innovative class of novel 2-aryl-5-(1-aryl-1H-pyrazol-3-yl)-1,3,4-oxadiazoles 5i–w have been synthesized from ring transformation using L-proline as an organocatalyst. This novel method using organocatalyst is a splendid example of the green reaction with improved yields. The molecular docking analysis of compounds 5i–w were investigated with enoyl-acyl carrier protein reductase (InhA) enzyme (PDB ID: 4TZK) as anti-tubercular target molecules. The docking study implied that the synthesized compounds exhibited favorable binding modes and affinity. Further, the anti-tubercular activity was investigated against Mycobacterium tuberculosis (MTB) H37Rv strain which demonstrated that the compounds 5i, 5j, 5k, and 5l exhibited excellent activity at the 6.25 µg/ml concentrations, whereas the compounds 5m, 5n, 5o, 5s, and 5w have shown the activity at 12.50 µg/ml concentration, respectively.

Synthesis of new morpholine-benzimidazole-pyrazole hybrids as tubulin polymerization inhibiting anticancer agents

The synthesis of some new morpholine-benzimidazole-pyrazole hybrids (8a-o) and their in vitro anticancer activity against three human cancer cell lines like breast (MCF7), prostate (PC3) and lung (A549) was reported herein. Among all the hybrids, compound 8k displayed superior activity against all the cell lines than the standard drug etoposide. As well, compounds 8d, 8e, 8f and 8m showed most promising activity as compared to the positive control. Furthermore, compounds 8e, 8f, 8k were found to be 2 to 3 times more potent in inhibiting tubulin polymerization as compared to standard combretastatin A-4 (CA-4). Finally two in silico studies like molecular docking on α,β-tubulin (PDB ID-1SA0) and ADMET for the active compounds 8d, 8e, 8f, 8k and 8m were carried out, where, the results were found to be covenant with the corresponding anticancer data.

Design, synthesis and in vitro antimicrobial activity of fused pyridine-pyrimidine hybrids

The antimicrobial resistance (AMR) is defined as the rising global concern of infectious illnesses that are resistant to all known antimicrobial agents. The discovery of novel antimicrobial agents is required as microbial resistance increases. Due to this reason, we have synthesized a series of novel pyridine-pyrimidine derivatives ( 4a-o ) for the development of antimicrobial agents. The structures of these bioactive molecules were determined using IR, 1 H NMR, 13 C NMR, and mass spectroscopy. The titled compounds were tested for antimicrobial activity against various bacterial and fungal strains using chloramphenicol and griseofulvin as standard drugs. Compounds 4b, 4d and 4m exhibited excellent antibacterial activity with MIC = 62.5 µg/mL against E. coli, S. aureus and S. pyogenes respectively. Compounds 4g and 4o showed prominent activity against C. albicans with MIC value of 250 µg/mL.

Identification of (S)-1-(2-(2,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea as a potential anti-colorectal cancer agent

In our previous study, 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea (1) was obtained as a potent tyrosine kinase inhibitor. Further structural optimization was performed in this investigation, and a series of novel quinoline derivates were designed, synthesized and evaluated for their biological activity. Among them, compound 8m possessed nanomolar c-Met and Ron inhibitory activity, with IC50 values of 4.32 nM and 2.39 nM, respectively. Kinase profile study demonstrated that it could also inhibit ABL, PDGFRβ, AXL, RET, and FLT3 with submicromolar potency. It also exhibited moderate to excellent cytotoxic activity against different types of human cancer cell lines, especially against COLO 205 cells (IC50 = 0.035 μM) which was remarkably superior to that of Cabozantinib (IC50 = 6.6 μM) and Fruquintinib (IC50 > 10.0 μM). Compared to ( ± )-8m, isomer (S)-8m and (R)-8m showed similar kinase inhibitory activity against c-Met/RON and in vitro anticancer activity against COLO 205 cells. Differently, compound (S)-8m showed an over 238-fold selectivity toward COLO 205 (IC50 = 0.042 μM) cells to FHC cells (IC50 > 10.0 μM), which indicated its low cytotoxicity against human normal tissue cells. Flow cytometry study demonstrated that compound (S)-8m could significantly induce apoptosis in COLO 205 cells in a dose-dependent manner. Cell cycle arrest assays showed that compound (S)-8m could not arrest the cell-cycle progression due to the massive dead cells.

Microwave-assisted synthesis of novel sulfonamide-based compounds bearing α-aminophosphonate and their antimicrobial properties

A series of α-aminophosphonates (3a-3m) bearing the sulfisoxazole moiety was synthesized through one-pot Kabachnik-Fields reaction of sulfisoxazole, diethyl phosphite (DEP) and substituted aldehydes using bismuth (III) triflate [Bi(OTf)3] as a catalyst under microwave reaction conditions. The novel compounds are identified by their spectroscopic data and confirmed by X-ray diffraction studies of diethyl (4-chlorophenyl)(4-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)phenylamino) methylphosphonate 3g. The antimicrobial properties of the synthesised agents were examined against a range of bacterial species and C. albicans yeast. Some of the synthesised agents, 3j, 3l and 3m, exhibit potent antimicrobial activities against the five pathogenic microorganisms used in the investigation. Compound 3m is the most promising agents among all the synthesized derivatives, showing a potent and broad-spectrum antibacterial activity. The MIC values are 94.2 and 205.7 µM for 3m and sulfisoxazole, respectively for S. typhi (about 2.1 times potency). The MIC values are 102.8 and 187.0 µM for 3m and sulfisoxazole, respectively for L. monocytogenes. The observed biological properties are explained and supported by QSAR models.

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives.

A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k–3m. Thus, compounds 3k–3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.

Synthesis, molecular docking, anti-cancer activity, and in-silico ADME analysis of novel spiroacenaphthylene pyrrolizidine derivatives

A short and efficient multicomponent sequence for synthesizing spiroacenaphthylene pyrrolizidine analogs 5a-svia 1,3-dipolar cycloaddition reaction of azomethine ylide with chalcones 4a-s without any catalyst. Synthesized compounds 5a-s were characterized by spectral data and single crystal X-ray diffraction study. In-vitro anti-proliferative activity of compounds 5a-s against K562-leukemia showed that compounds 5e, 5i, 5l, 5m and 5o have an IC50 value of 54.07, 47.48, 50.57, 53.85 and 49.57 µg/ml respectively and exhibited H-bonding with LYS 875 in the molecular docking studies against the 2J5F protein and showed favourable in-silico ADME properties. Compound 5o showed favourable in-vitro anti-proliferative activity against K562-leukemic cell line and favourable in-silico ADME properties. It can serve as a template to develop further as a lead molecule and act as a tyrosine kinase inhibitor.

Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kα inhibitors.

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC50 value of 6.34 μM and compound 8m displayed an IC50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 μM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamicssimulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds.

Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid (a), was consecutively transformed into benzoate (1), hydrazide (2), semicarbazide (3), and N-furfuryl 5-(4-chlorobenzyl)-4H-1,2,4-triazole (4), which when further merged with electrophiles (6a–o) resulted in end products (7a–o). The structural elucidations of the newly synthesized compounds (7a–o) were carried out by Fourier transform infrared, 1H-, 13C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds (7a–o) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k, 7o, 7m, 7b, and 7i demonstrated potent activities (IC50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy

The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC1&6 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.

Design, Synthesis, and Structural Characterization of Thioflavones and Thioflavonols as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies.

To find new potential tyrosinase inhibitors, a diverse range of 2-arylchromone-4-thione derivatives (2a–2p) were designed and synthesized by employing a multistep strategy, and the newly synthesized compounds, for the first time, were screened in vitro for their tyrosinase inhibitory activity. In this context, the newly synthesized compounds (2a–2p) were characterized using a combination of several spectroscopic techniques including Fourier transform infrared, UV–vis, 1H NMR, and 13C NMR spectroscopies and electron ionization–mass spectrometry. All the target compounds were potent against tyrosinase as compared to the standard inhibitor kojic acid (half-maximal inhibitory concentration (IC50) = 12.6 ± 0.6 μM). The compounds (2a–2p) produced IC50 values in the range from 1.12 ± 0.04 to 5.68 ± 0.13 μM. Among the synthesized 4-thioflavones and 4-thioflavonols, the compound 2n exhibited excellent tyrosinase inhibitory activity with the lowest IC50 of 1.12 ± 0.04 μM that could be recommended as potential lead candidates to cure tyrosinase-mediated hyperpigmentation in the future. A kinetic study of compound 2n revealed that compound 2n inhibited tyrosinase in a competitive mode. Furthermore, the nontoxic performance of the most beneficial compounds ranging from 1 to 25 g/mL was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test method for A375 human melanoma cells for the highly efficient target compounds (2m, 2n, 2o, and 2p). Moreover, a molecular modeling study was performed against tyrosinase enzyme (2Y9X) to check the binding interactions of the synthesized compounds (2a–2p) against the target protein. Furthermore, quantitative structure-activity relationship studies were conducted based on an antityrosinase assay. The value of the correlation coefficient (R2) 0.9997 shows that there was a good correlation between (2a–2p) structures and selected properties. The geometry optimization of all complexes was performed by using Gaussian 09. Additionally, a drug-likeness research was used to establish the potent analogues’ positive action as a new antityrosinase agent (2n, 2o, and 2p).