Compounds 3e Research Articles

Experimental Antioxidant Activities of Synthetic 3,4-Dihydropyrimidine Derivatives.

The synthesized of five new pyrimidine derivatives was prepared from the condensation in one pot reaction of ethyl acetoacetate, substituted aromatic aldehydes, urea, and FeCL3.6H2O, with 5 to 10 drops of hydrochloride acid as catalyst in reflexing ethanol. The yield of the product was found to be in the range of 55 to 90%. The antioxidant efficiency of synthesized compounds was estimated by using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) method, hydroxyl method, nitric oxide method, and superoxide radical scavenging assay method. The compounds 6a, 6e, and 6c demonstrated considerable radical scavenging activity, resulting in the presence of electron-donating substituent on replaced aldehydes. The confirmation compounds by spectral data by proton and 13C-nuclear magnetic resonance, infrared spectra, and MS spectra.

Synthesis, Structural, DFT studies, Biological Effectiveness, and Molecular Docking Aspects of Multitarget Novel N-(4-Phenylthiazol-2-yl)hydrazine carboxamide Hybrids as COX inhibitors, Anti-TB, and Anti-oxidant activity

We herein report, a series of N-(4-phenylthiazol-2-yl)hydrazinecarboxamide based multitarget compounds 3(a-i) were designed and synthesized. Ten compounds 2, and 3(a-i) were characterized by FTIR, NMR (1H and 13C), and mass analysis and subsequently, tested for their potential COX inhibitors, anti-TB, and anti-oxidant activities. The physicochemical and ADME studies for newly synthesized compounds were disclosed. The DFT calculations were taken for the selected molecules using CAM-B3LYP hybrid functional with a 6–31+g(d) all-electron basis set using the Gaussian 09 package. The compounds 3d, 3e, and 3f recognized outstanding COX-II inhibitions with IC50 values of 0.62, 0.78, and 0.72 μM compared to standard drugs. The compounds 3d, 3e, and 3f showed outstanding anti-TB activity with a MIC value of 0.78μg/mL. The compound 3d, and 3f attested outstanding antioxidant activity at 10 μg/mL with a rate of inhibition of 68.12%, and 68.85% respectively. Finally, the molecular docking studies carried out with cyclooxygenase-2 (PDB ID: 6COX), M. tuberculosis enoyl reductase (INHA) (PDB ID: 4TZK), and cytochrome c peroxidase (PDB ID: 2×08), for all the newly synthesized derivatives. Finally, selected compounds were taken for their molecular dynamic studies.

Synthesis and Evaluation of Thiazolyl-indole-2-carboxamide Derivatives as Potent Multitarget Anticancer Agents.

Cancer is a complex disease driven by the dysregulation of multiple signaling pathways and cellular processes. The development of compounds capable of exerting multitarget actions against these key pathways involved in cancer progression is a promising therapeutic approach. Here, a series of novel (E/Z)-N-(4-(2-(2-(substituted)hydrazineyl)-2-oxoethyl)thiazol-2-yl)-1H-indole-2-carboxamide derivatives (6a-6z) were designed, synthesized, and evaluated for their biological activity. Compounds 6e, 6i, 6q, 6v, 7a, and 7b exhibited exceptional cytotoxicity against various cancer cell lines, particularly 6i (IC50 = 6.10 ± 0.4 μM against MCF-7 cell lines) and 6v (IC50 = 6.49 ± 0.3 μM against MCF-7 cell lines). These potent compounds inhibited key protein kinases like EGFR, HER2, VEGFR-2, and CDK2, induced cell cycle arrest at the G2/M phase, and promoted apoptosis. Docking studies revealed improved binding affinity of 6i and 6v with target proteins compared to reference drugs. These findings highlight the promising potential of 6i and 6v as multitarget cancer therapeutics deserving further development.

Novel triazine-tyrosine hybrids containing thiyazol or pyridine fragment as anti-multiple sclerosis agents: Design, synthesis, biological evaluation, and molecular docking study

In this study novel triazine-tyrosine hybrids containing thiazole or pyridine fragments were introduced as anti- Multiple Sclerosis agents. The compounds were designed according to the structure of the Sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator, fingolimode. At first, docking studies was performed using crystal structures of S1P1 and Sphingosine-1-phosphate receptor subtype 3 (S1P3) to theoretically identify the selectivity of the compounds towards the S1P1 isoform. The docking results showed better binding energy (lower ΔGb) and therefore higher selectivity for S1P1 receptor than S1P3 receptor. Subsequently the designed compounds were synthesized according to proper chemical reactions and structurally analyzed with FTIR and NMR spectrophotometers. Considering the importance of the S1P1 receptor in release of lymphocytes and therefore inflammation produced in Multiple Sclerosis disease, the synthesized compounds were investigated to study lymphocyte reduction in an animal model. Compound (8e) with 2-mercaptobenzothiazole substitution at doses of 1 and 3 mg/kg showed significant reduction effect on the percentage of lymphocytes (68.80 %, 56.75 %) compared to the fingolimod (65.73 %, 20.66 %), as the positive control group.

Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful “multitarget-directed drug” for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.

A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent.

The aim of the present investigation is to identify effective anti-HIV drugs through the in-silico virtual screening of the coumarin pharmacophore with or without substituents. Virtual screening started with target identification through computation docking and interactions, binding affinity through molecular dynamics, and the ADMET profile through the use of various enzymes. The target study suggests that the target is involved in various stages of HIV replication and in determining the ways in which non-nucleoside reverse transcriptase inhibitors (RTIs) influence it. The interaction pattern and simulation study conclude the specific affinity of coumarin pharmacophore to the HIV's reverse transcriptase enzyme, especially 3HVT. Moreover, the amide linkage worked as a synergistic bridge to provide more interaction to the pharmacophore. The initial results led to the determination of 83 virtual amide-like molecules, which were screened through docking and MD studies (100 ns) on the best-suited enzyme HIV's reverse transcriptase enzyme, such as PDB ID "3HVT". The virtual screening study revealed the high affinity of compounds 7d and 7e with the lowest IC50 values of 0.729 and 0.658 μM; moreover, their metabolism pattern study, toxicity, and QED values in a range of 0.31-0.40 support a good drug candidate. The two compounds were also synthesized and characterized for future in vitro and in vivo studies. The in silico-based descriptor of compounds 7d and 7e indicates the potential future and provides the best two molecules and their synthetic route for the development of a more effective drug to combat HIV/AIDS epidemics.

Exploring the Therapeutic Potential of Coumarin-thiazolotriazole Pharmacophores for SARS-CoV-2 Spike Protein through In-vitro and In-silico Evaluation.

The pandemic caused by SARS-CoV-2 significantly impacted human life around the globe. Numerous unexpected modifications of the SARS-CoV-2 genome have resulted in the emergence of new types and have caused great concern globally. Inhibitory effects of bioactive phytochemicals derived from natural and synthetic sources are promising for pathogenic viruses. in vitro and in silico techniques were used in the current study to identify novel inhibitors of coumarin clubbed thiazolo[3,2-b][1,2,4]triazoles against the SARS-CoV-2 spike protein. Interestingly, all the tested molecules demonstrated substantial inhibition of spike protein with 91.81-57.90% inhibition. The spike protein was remarkably inhibited by compounds 6k (91.83%), 6j (89.75%), 6m (87.69%),6i (86.60%), 6l (85.40%), 6h (84.70%), 6l (84.70%), 6g (83.40%), 6b (82.60%), 6f (81.90%), while compounds 6d 6a, 6c, and 6e exhibited significant activity against spike protein with 79.60%, 77.10%, 75.30%, and 57.90% inhibition, respectively. The binding mechanism of these novel inhibitors with spike protein was deduced in silico, which reflects that the active molecules firmly bind with the receptor binding domain (RBD) of spike protein, thereby inhibiting its function. The combined in vitro and in silico investigations unfold the therapeutic potential of coumarin-thiazolotriazole scaffolds in the treatment of SARS-CoV-2 infection.

Synthesis, cytotoxic evaluation, and in silico studies of novel benzenesulfonamide-thiazolidinone derivatives against colorectal carcinoma

Thirteen new benzenesulfonamide derivatives containing 4-thiazolidinone were synthesized. Their cytotoxic properties were tested on colorectal carcinoma (HT-29, DLD-1, COLO-205) and normal colon fibroblast (CCD-986Sk) cell lines. Compounds 3l (IC50=114.62 µM), 3a (IC50=25.82 µM), 3k (IC50=30.99 µM), and 3i (IC50=62.94 µM) showed the highest cytotoxicity on HT-29, DLD-1, COLO-205, and CCD-986Sk cell lines, respectively. Compound 3e (IC50=1075.4 µM) exhibited the least cytotoxicity against CCD-986Sk. The apoptosis profile of 5-FU at 5 µM was similar to that of compound 3e at 30 µM. Molecular docking and MD simulations showed stable interactions for compounds 3i and 3e. Molecular docking and MD simulations revealed that compounds 3i and 3e exhibit stable interactions with key cancer-related protein targets, particularly TGFβ2. These interactions suggest their potential as therapeutic agents. The predicted ADME parameters further highlighted compounds 3e and 3i for their favorable lipophilicity, solubility, permeability, and oral absorption profiles, supporting their promise as candidates for future drug development.

Furan-Triazine clubbed Schiff base derivatives: Computational insight and empirical precision against A-549 and MDA-MB-468 Carcinoma cells

The purpose of this effort is to generate a range of 1,3,5-triazine substituted furan-2-carbaldehyde Schiff base derivatives (5a-5h) that may be employed as anticancer drugs. The effectiveness of recently synthesised compounds was evaluated in vitro against A-549 lung cancer cell line and MDA-MB-468 breast carcinoma cell line, providing an in-depth evaluation of their possible therapeutic effect on these particular cancer types. Compounds 5e and 5g were found to be the most effective of this series in targeting A-549 lungs cancer cells with IC50 values of 6.33 and 0.31 μM, respectively against the standard drug pictilisib (IC50 1.66 μM), while compounds 5a and 5e were found to be the most promising in targeting MDA-MB-468, with IC50 values of 3.97 and 6.38 μM, respectively, against pictilisib (IC50 3.60 μM). To understand their interaction with the essential proteins involved in the progression of cancer, molecular docking studies were carried out, which gave information about their putative mechanisms of action. Furthermore, molecular dynamics simulations were utilised to analyse the stability and dynamic behaviour of the most active compounds inside the protein binding sites. The study revealed several compounds demonstrating notable anticancer activity, offering encouraging possibilities for their continued development and improvement as novel anticancer medications.

Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents.

Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure-activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.

Synthesis, Molecular Docking, and Anticancer Screening of Ester-based Thiazole Derivatives.

This study investigates the potential of five compounds as novel anticancer agents. We examined their efficacy, mechanisms of action, and impact on various cancer cell lines, through a comprehensive set of experiments. Notably, compound 3e demonstrated superior activity compared to the positive control cisplatin, with a GI50 value of 6.3±0.7 μM against the breast cancer cell line (MCF-7). Compound 3b also displayed remarkable growth inhibition, yielding GI50 values of 8.7±0.2 μM (MCF-7) and 8.9±0.5 μM against the colon cancer cell line (HCT-116). Cell count experiments further confirmed the potent inhibitory effects of compounds 3e, 3b, and 3c on MCF-7 and HCT-116 cell growth. Compound 3e demonstrated a reduction of 55-60 % at GI50 and complete inhibition (100 %) at 2x GI50. Compound 3b exhibited 50-55 % reduction (GI50) and 90-95 % inhibition (2x GI50) in HCT-116 cells. Compound 3c displayed 75-80 % inhibition (2x GI50) and 35-40 % inhibition (GI50) in HCT-116 cells. In-depth mechanistic investigations unveiled valuable insights into the mode of action of compound 3e. The cell-cycle assay demonstrated G2/M phase arrest, DNA damage, and caspase-mediated apoptosis in both MCF-7 and HCT-116 cells. Caspase activation indicated a significant increase in apoptosis following exposure to compound 3e. Furthermore, compound 3e induced reactive oxygen species (ROS) production, influencing HCT-116 and MCF-7 cells differently. Elevated ROS production in HCT-116 cells and distinct effects in MCF-7 cells contribute to a deeper understanding of the cytotoxic mechanisms of compound 3e. Overall, these findings highlight the potential of the investigated compounds, particularly compound 3e, as effective inducers of apoptosis in cancer cells. Mechanistic insights into cell cycle arrest, caspase-mediated apoptosis, and ROS modulation provide a comprehensive understanding of their cytotoxic effects. This study offers significant contribution to the development of promising anticancer agents and their therapeutic applications.

Organocatalytic[3 + 2]Cycloaddition: Synthesis of Quinazoline Containing Sulfonyl 1,2,3‐Triazoles as Potent EGFR Targeting Anti‐Breast Cancer Agents

ABSTRACTA general strategy was developed for the synthesis of new fully decorated 1,2,3‐triazoles (4a–4m and 5a–5g) containing quinazolines from 1‐(4‐nitrophenyl)‐2‐(quinazolin‐8‐ylsulfonyl) ethan‐1‐one and several azides using Ramachary organocatalytic azide‐ketone cycloaddition method. This reaction is reported for the synthesis of fully substituted sulfonyl‐1,2,3‐triazolyl quinazolins at a temperature of 100°C and the yields of the products produced are satisfactory to excellent. In vitro anticancer activity of all these derivatives demonstrated that six compounds, 4d, 4f, 4i, 4j, 5d, and 5e, were effective against two human breast cancer cell lines, MCF‐7 and MDA‐MB‐231. Compounds 4f, 4j, and 5d had more action against both cell lines than Erlotinib. Later, the findings of inhibitory assays of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e against the tyrosine kinase EGFR revealed that compound 5d proved more potent than the reference erlotinib, while 4f and 4j had comparable efficacy. In silico molecular docking studies were also performed on six strong medicines to identify interactions with the EGFR receptor, and the energy estimations were shown to be comparable with the observed IC50 values. Ultimately, using SWISS/ADME and pkCSM, the in silico pharmacokinetic profile of potent compounds 4d, 4f, 4i, 4j, 5d, and 5e was predicted. All of the compounds precisely followed the principles established by Lipinski, Veber, Egan, and Muegge.

Design, synthesis, and in silico insights of novel N’-(2-oxoindolin-3-ylidene)piperidine-4-carbohydrazide derivatives as VEGFR-2 inhibitors

Vascular endothelial growth factor (VEGF) is a crucial key factor in breast tumorigenesis. VEGF plays an important role in angiogenesis, tumor proliferation, and metastasis. Herein, we report the design and synthesis of twenty-one novel piperidine/oxindole derivatives as potential VEGFR-2 inhibitors. The designed compound library aimed to occupy the binding site of VEGFR-2 in a similar binding pattern to that of the reference VEGFR-2 inhibitor Sorafenib. The synthesized compounds were biologically evaluated for their cytotoxic effects against two breast cancer cell lines (MCF-7 and MDA-MB-468). Compounds 12e and 6n were the most potent cytotoxic derivatives against the former and the latter cell lines, showing IC50 values of 8.00 and 0.60 µM, respectively. Furthermore, all the synthesized compounds were evaluated for their inhibitory activities towards VEGFR-2, with compound 12e showing the most potent activity with an IC50 value of 45.9 nM, surpassing the reference standard Sorafenib (IC50 = 48.6 nM). Additionally, compound 6n emerged as the top performer when tested with the other most promising compounds for their cytotoxic effects on HUVEC (IC50 = 28.77 nM). The designed library of compounds was subjected to molecular docking and molecular dynamic simulations, which revealed key binding interactions within the VEGFR-2 active site, including hydrogen bonding with Cys919, Glu885, and Asp1046 residues. Moreover, in silico predictions of physicochemical and pharmacokinetic properties for the target compounds indicated favorable drug-like characteristics.

Design, Synthesis, Investigation, and Biological Activity Assessments of (4-Substituted-Phenyl)-N-(3-morpholinopropyl)-3-phenylthiazol-2(3H)-imine Derivatives as Antifungal Agents.

In this study, a series of novel thiazol-2(3H)-imine (2a-2j) were designed, synthesized, and characterized by means of 1H NMR, 13C NMR, and HRMS spectral analyses. In vitro antifungal activity was performed using a modified EUCAST protocol. Two of the synthesized compounds (2d and 2e) showed activity against Candida albicans and Candida parapsilosis. Compound 2e showed activity against C. parapsilosis (MIC50 = 1.23 μg/mL) for 48 h. This value is very similar to ketoconazole. The dynamic analysis of the potential compounds 2d and 2e revealed notable stability while interacting with the 14α-demethylase enzyme substrate. The absorption, distribution, metabolism, and excretion (ADME) studies of the candidate compound showed acceptable ADME parameter data and verified their drug-likeness characteristics. According to the results of this study, compound 4-(4-fluorophenyl)-N-(3-morpholinopropyl)-3-phenylthiazol-2(3H)-imine (2e) and its derivatives as 14α-demethylase inhibitors can be used as a new antifungal for further structural improvements and additional research.

Design, Synthesis and In-Vitro Antimicrobial and Cytotoxic Activity Screening of 5-Carboxamide Substituted 3, 4-Dihydropyrimidine-2 (1H) Ones

This paper describes the synthesis and in vitro biological evaluation of new compounds designated as 5(a-h) and 8(a-f). These compounds were synthesized by the reaction of thiazole derivative (3) or thiadiazole derivative (7) with urea and various aromatic aldehydes 4(a-h) in ethanol. The structures of the synthesized compounds were checked by IR,1H,13C NMR, and Mass spectroscopy. The antibacterial and antifungal activities of the compounds were evaluated against Escherichia coli (Gram-negative), Staphylococcus aureus (Gram-positive), and Candida albicans (fungus) using agar well diffusion, minimum inhibitory concentration (MIC), and minimum bactericidal/fungicidal concentration methods. The cytotoxic activities of these compounds against HT-29 and A-549 cancer cell lines were assessed in vitro by the MTT method. Our studies showed compounds 8c and 8f to have the most expressed antibacterial activity against S. aureus, while compounds 8c and 8d were the most potent against E. coli. Compounds 5h and 8e showed the highest antifungal activity against C. albicans, and compound 5f showed the most potent activity against the tested cancer cell lines.

Synthesis, antifungal activity, and 3d-QSAR study of L-carvone-based pyrazole-oxime ester compounds

Natural products can provide versatile substructures with potential bioactivity and biocompatibility for exploring bioactive compounds. Herein, to explore novel natural product-derived antifungal agents, 21 unreported L -carvone-based pyrazole-oxime ester compounds 6a-6u were synthesised using L-carvone as raw material, and structurally characterised by means of FT-IR,1H NMR,13C NMR, and HRMS. The results of the in vitro bioactivity tests showed that the target compounds exhibited certain antifungal activity against the eight tested plant fungi at the concentration of 50 mg/L, especially for Physalospora piricola. The inhibition rates of compounds 6e (R = m-Cl) and 6c (R = m-F) against P. piricola were 88.3% and 83.9%, respectively, both better than that of the positive control chlorothalonil. Compound 6e (R= m-Cl) with the most significant antifungal activity deserves further investigation as the potential leading compound. In addition, the structure-activity relationships (SARs) of the target compounds were investigated by establishing an effective three-dimensional quantitative structure-activity relationship (3D-QSAR) model.

Design, synthesis, and evaluation of a novel TRAIL-activated HDAC6 inhibitor for the treatment of pulmonary fibrosis

Pulmonary fibrosis (PF) is a common, severe, chronic, and progressive pulmonary interstitial disease characterized by rapid disease progression and high mortality. Despite the Food and Drug Administration (FDA)’s approval of two antifibrotic drugs, nintedanib and pirfenidone, effectively halting the progression of pulmonary fibrosis remains challenging. Histone deacetylase (HDAC) inhibitors have indeed emerged as an important class of antitumour drugs. However, their application in the treatment of fibrotic diseases is still relatively limited. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has the potential to inhibit fibrotic processes by inducing fibroblast apoptosis. In this study, we designed and synthesized a series of histone deacetylase 6 (HDAC6) inhibitors that activate TRAIL, among which compound 7e exhibited potent inhibitory activity against HDAC6, with an IC50 of 42.90 ± 4.96 nM and superior antiproliferative effects on fibroblasts. Therefore, we further investigated its anti-pulmonary fibrosis effect in mouse models of both idiopathic pulmonary fibrosis (IPF) and silicosis. Our results suggest that compound 7e is a promising candidate for the treatment of pulmonary fibrosis.

Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies.

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.

Experimental and computational profiling of novel bis-Schiff base derivatives bearing α-naphthalene moiety as potential tyrosinase inhibitors

A library of novel bis-Schiff base derivatives (2a-u) of α-naphthalene moiety was successfully synthesized by four step reactions. Following structural elucidation, these products were evaluated for their in vitro tyrosinase inhibitory potential. In the series, nine derivatives (2e, 2r, 2t, 2 g, 2 u, 2p, 2a, 2d, and 2 h) attributed excellent inhibitory activity in the range of IC50 values from 2.3 ± 1.7 to 17.6 ± 0.9 µM superior to the standard drug kojic acid. Similarly, four compounds showed significant activities near to the standard while the remaining eight compounds displayed good to moderate inhibition with IC50 values from 29.3 ± 2.9 to 63.2 ± 1.1 µM. The molecular docking investigations for most active compounds (2e, 2r, 2t, 2 g, 2 u, 2p, 2a, 2d, and 2 h) form high stability in binding site of the tyrosinase active site, than standard kojic acid. Frontier molecular orbitals, such as HOMO and LUMO to show the charge transfer from molecule to biological medium and MEP map to show the chemically reactive zone appropriate for drug action, are calculated using TD-DFT. Besides, the drug-likeness prediction showed that these compounds showed a desirable property, such as high intestinal absorption, large volume of distribution, good BBB penetration, and low toxicity. These bis-Schiff bases have a high oral bioavailability, which can categorized as a unique drug candidate in future.

Exploring the anticancer properties of indole pyrimidine derivatives: Synthesis, structural insights, docking analysis, and in vitro evaluation

The nitrogen containing heterocyclic and chalcones moiety widely recognized as favorable combination of diagnostic and therapeutic facilities in medicinal chemistry. In particular, indole analogs play a very important medicinal role in pharmacology activities, hence, drugs like pindolol, indomethacin, oxypertine, ellipticine, arbidol and ate viridine are well known in market. In this view, the title compounds 4(a-j) were synthesized in good yield. The purified compounds were explained by spectroscopic procedures (FT-IR, 1H NMR, 13CNMR, and LC-MS), and lastly, all synthetic compounds have in-vitro efficacy assessed against the HeLa human cervical cancer and MCF-7 human breast cancer cell lines, and their efficacy was compared to that of the well-known anticancer drug methotrexate (Methotrexate). Compounds 4a, 4b, 4c, and 4e from the series (4a-j) demonstrated the most notable inhibitory activity. The cytotoxicity evaluation of these newly synthesized compounds revealed that 4a, 4b, 4c, and 4e were the most toxic to HeLa cells, with IC50 values for growth inhibition of 20.41 ± 3.14, 23.54 ± 3.27, 24.77 ± 2.14, and 26.10 ± 1.58, respectively. These compounds exhibited an even stronger growth-inhibitory effect on MCF-7 cells, with IC50 values of 18.84 ± 2.69, 19.45 ± 3.14, 22.83 ± 2.68, and 21.80 ± 1.68, respectively. In comparison, methotrexate (Methotrexate) showed IC50 values of 28.29 ± 1.0 for HeLa cells and 45.08 ± 2.61 for MCF-7 cells. Additionally, compounds 4a, 4b, 4c, and 4e played a crucial role in interacting with the catalytic domain of PDE3, demonstrating IC50 values for PDE3A inhibition of 8.05 ± 1.27, 7.55 ± 2.14, 15.09 ± 1.54, and 17.12 ± 3.14, respectively. These results are compared with Cilostazol, a known PDE inhibitor, which exhibited an IC50 of 0.00368 ± 3.14. In-silico studies revealed that compounds (4a, 4b, and 4c) are comparatively very efficient in binding with PDE3A which was further validated with MMGBSA and MDSs.