Compounds 4d Research Articles

Development of novel antibiotics derived from pyridazine: Synthesis, spectroscopic characterization, in vitro antimicrobial activity and molecular docking studies

In light of the increasing antibiotic resistance, it is crucial to discover new antimicrobial medications. Pyridazines are frequently investigated in research for the development of new chemical entities with enhanced therapeutic properties. Their structure allows for significant flexibility in the attachment of various functional groups, which is essential for drug discovery.Our work focuses on synthesizing new pyridazine derivatives (7a, 7b, 7c and 7d) through coupling reactions with various amino esters. The structures of these compounds have been analyzed using spectroscopic measurements including 1H, 13C NMR, IR, and mass spectroscopy. The compounds showed positive effects against two bacterial strains: Escherichia coli: ATCC25922 and Staphylococcus aureus: CIP543154. Molecular docking results of the protein 7AZ5 indicated significant affinities with these molecules through hydrogen bonds. Compounds 7a and 7d demonstrated the highest binding energies and the best antimicrobial activity, suggesting their potential as a model for creating novel and potent antimicrobial compounds.

Design, Synthesis and Cytotoxic Studies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer

Background: The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4- anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients. Objective: We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines. Methods: Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives were performed, based on the docking score and was characterized by various spectroscopic methods. Further, in vitro anti-cancer activity was performed using MTT assay on different cancer cell lines. Results: Molecular docking analysis [EGFRT790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC50 values of 4.88 ± 0.13, 4.38 ± 0.08 & 11.97 ± 0.14 μM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines. Conclusion: The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.

Synthesis, anti-microbial, and docking studies of functionalized chromenyl phosphonates using ionic liquid catalyst.

Synthesis of functionalized chromenyl phosphonates by the reaction among 2-hydorxybenzaldehydes, dicyanoethane, and dialkyl phosphonates that was promoted by choline hydroxide ionic liquid catalyzes the simultaneous, Knoevenagel, Pinner, and phospha-Michael reactions, under neat condition at room temperature. Important phosphorus-containing compounds can be produced at a reasonable cost because of the mild reaction conditions and the inexpensive promoter choline hydroxide. Furthermore, the desired products can be obtained without the need for any extraction or chromatography steps. An alternate technique for the simple and high-yield synthesis of functionalized chromenyl phosphonates is offered by this protocol. The synthesized compounds were studied by anti-microbial activity and docking studies. The title compounds molecular docking investigations demonstrated their efficacy as therapeutic agents against DNA Gyrase B and Aspergillus niger endoglucanase in both antibacterial and antifungal inhibition, and they identified compounds 4a, 4d, 4l, 4p, and 4q as promising candidates for microbial treatment, with binding affinities ranging from -6.9 to -7.4kcal/mol.

Design, Synthesis, Anti-Cancer, Anti-inflammatory and In Silico Studies of 3-Substituted-2-Oxindole Derivatives.

This study focuses on the design and synthesis of 3-substituted-2-oxindole derivatives aimed at developing dual-active molecules with anti-cancer and anti-inflammatory properties. The molecules were designed with diverse structural and functional features while adhering to Lipinski, Veber, and Leeson criteria. Physicochemical properties were assessed using SWISSADME to ensure drug-likeness and favourable pharmacokinetics. Multistep synthetic procedures were employed for molecule synthesis. In vitro evaluations confirmed the dual activity of the derivatives, with specific emphasis on the significance of dialkyl aminomethyl substitutions for potency against various cell lines. 4 a exhibited GI50 value 3.00E-05 against MDA-MB-231, 4 b has shown GI50 value 2E-05 against MDA-MB-231, 4 c has shown GI50 value 6E-05 against VERO, 4 d has shown GI50 value 8E-05 each against both the MDA-MB-231 and MCF-7 and 4 e has shown GI50 values 2E-05 and 5E-05 each against both the MCF-7 and VERO. The analysis indicates that compounds 3 c (71.19 %), 3 e (66.84 %), and 3 g (63.04 %) exhibited significant anti-inflammatory activity. Additionally, in silico binding free energy analysis and interaction studies revealed significant correlations between in vitro and computational data, identifying compounds 4 d, 4 e, 3 b, 3 i, and 3 e as promising candidates. Key residues such as Glu917, Cys919, Lys920, Glu850, Lys838, and Asp1046 were found to play critical roles in ligand binding and kinase inhibition, providing valuable insights for designing potent VEGFR2 inhibitors. The Quantum Mechanics-based Independent Gradient Model analysis further highlighted the electronic interaction landscape, showing larger attractive peaks and higher electron density gradients for compounds 4 d and 4 e compared to Sunitinib, suggesting stronger and more diverse attractive forces. These findings support the potential of these compounds for further development and optimization in anticancer drug design.

Derivatization of Abietane Acids by Peptide-like Substituents Leads to Submicromolar Cytotoxicity at NCI-60 Panel.

Natural compounds, including diterpenoids, play a critical role in various biological processes and are recognized as valuable components in cancer treatment. Isocyanides multicomponent reactions (IsMCRs) are one of the effective methods to obtain adducts at the carboxyl group with a peptide-like substituent. In this study, dehydroabietic acid and levopimaric acid diene adducts as the starting scaffolds were modified by the multicomponent Passerini (P-3CR) and Ugi (U-4CR) reactions to afford α-acyloxycarboxamides and α-acylaminocarboxamides. A group of twenty novel diterpene hybrids was subjected to NCI in vitro assessment, and a consistent structure-activity relationship was established. Eleven of the synthesized derivatives inhibited the growth of cancer cells of 4 to 39 cell lines in one dose assay, and the most active were derivatives 3d, 9d, and 10d holding a fragment of 1a,4a-dehydroquinopimaric acid. They were selected for a five-dose analysis and demonstrated a significant antiproliferative effect towards human cancer cell lines. The outstanding cytotoxic activity was observed for the P-3CR product 3d with growth inhibitory at submicromolar and micromolar concentrations (GI50 = 0.42-3 μM) against the most sensitive cell lines. The U-4CR products 9d and 10d showed selective activity against all leukemia cell lines with GI50 in the range of 1-17 µM and selectivity indexes of 5.49 and 4.72, respectively. Matrix COMPARE analysis using the GI50 vector showed a moderate positive correlation of compound 3d with standard anticancer agents that can influence kinase receptors and epidermal growth factor receptors (EGFRs). The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents. The obtained results indicate that these new hybrids could be useful for the further development of anticancer drugs, and 1a,4a-dehydroquinopimaric acid derivatives could be recommended for in-depth studies and the synthesis of new antitumor analogs on their basis.

Emerging therapeutics: The imidazo[1,2-b]pyridazine scaffold as a novel drug candidate for eumycetoma, a neglected tropical disease

Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC50 ≤ 5 μM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC50 of 0.9 μM, in the same order then itraconazole (IC50 = 1.1 μM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies.

Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC50 of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.

Discovery of New Phenyltetrazolium Derivatives as Ferroptosis Inhibitors for Treating Ischemic Stroke: An Example Development from Free Radical Scavengers.

Ferroptosis is a promising therapeutic target for injury-related diseases, yet diversity in ferroptosis inhibitors remains limited. In this study, initial structure optimization led us to focus on the bond dissociation enthalpy (BDE) of the N-H bond and the residency time of radical scavengers in a phospholipid bilayer, which may play an important role in ferroptosis inhibition potency. This led to the discovery of compound D1, exhibiting potent ferroptosis inhibition, high radical scavenging, and moderate membrane permeability. D1 demonstrated significant neuroprotection in an oxygen glucose deprivation/reoxygenation (OGD/R) model and reduced infarct volume in an in vivo stroke model upon intravenous treatment. Further screening based on this strategy identified NecroX-7 and Eriodictyol-7-O-glucoside as novel ferroptosis inhibitors with highly polar structural characteristics. This approach bridges the gap between free radical scavengers and ferroptosis inhibitors, providing a foundation for research and insights into novel ferroptosis inhibitor development.

Synthesis, Antimicrobial Evaluation, and In Silico Studies of 2-Substituted-Phenyl-3-(5-Aryl/Heteroaryl Substituted Thiazol-2-yl) Thiazolidin-4-One Derivatives.

In a one-pot reaction involving 3-(2-aminothiazol-5-yl)-2H-chromen-2-one/5-(naphthalen-1-yl)thiazol-2-amines 5-6 with various substituted aldehydes and mercaptoacetic acid, we obtained the corresponding 2-(4-substituted-phenyl)-3-[5-(2-oxo-2H-chromen-3-yl)thiazol-2-yl] thiazolidin-4-ones 8(a-h) and 2-(4-substituted-phenyl)-3-[5-(naphthalen-1-yl)thiazol-2-yl] thiazolidin-4-ones 9(a-h). The antimicrobial activity of all compounds was evaluated against Pseudomonas aeruginosa (MTCC-424), Salmonella typhi (MTCC-531), Staphylococcus aureus (MTCC-737), and Candida albican (MTCC-227). Molecular docking further supported the findings, which showed that the compounds 8d and 9d had excellent antibacterial action against all tested pathogens.

Novel Thiazole-Hydrazide Derivatives and Their Anticancer Properties

Objective: Cancer is described as uncontrolled cell division, and it is a major problem in Türkiye, as well as around the world. Current treatment options are insufficient in some cases, particularly the treatment rate for lung cancer cases, which is very low. Meanwhile, current pharmaceuticals have several side effects, such as drug-drug interactions, and cognitive disorders. Additionally, developing drug resistance is a major problem for current and future management of the disease. Accordingly, the search for new molecules or alternative treatment options is actively achieved. Methods: In this study, eight novel thiazole-hydrazide analogs were designed and synthesized, and their structural elucidation was performed via HRMS, 1H-NMR, and 13C-NMR. Their biological activity profile was investigated on A549 lung carcinoma and MCF7 breast adenocarcinoma cells. To determine the selective cytotoxicity on cancer cells, they were also tested against NIH/3T3 healthy cell line. Besides that, an in silico study was performed to understand the binding modes of the compounds. Results: The results showed that in the serial 4f and 4g, the most bulky analogues, showed no inhibition against any cell type, even at the highest concentration tested. On the other hand, 4a, 4b, 4d, 4e, and 4h showed less cytotoxicity on healthy cells than A549 cells, so they exhibited significant cytotoxicity and a selective profile against A549 cancer cells. While they also inhibited MCF7 cells. The major point is that para-chlorophenyl analogs at the fourth position on thiazole (4a and 4d) displayed a better anticancer profile than ortho-chlorophenyl analogs. These two compounds were also investigated for their apoptotic effects using in silico studies. Both experimental and in silicon studies revealed that the combination of thiazole and hydrazinoacetyl has a significant impact against cancer cells, and in silico study also suggested that tri-substitute thiazole ring has anticancer potential that induced cancer cell death via apoptosis. Conclusion: Results of this study was presented that compound 4a was the most potent compound against lung cancer cells (A549) and 4d was the most potent compound against breast cancer cells (MCF-7). Furthermore, analyzing the molecular docking study for promising compounds (4a and 4d) suggested that interactions with the loop region residues have a pivotal role in inducing caspase-3 enzyme activity. It was concluded that hybridization of thiazole and hydrazinoacetyl moieties is responsible for the anticancer activity.

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Triflic acid-promoted Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives: Synthesis and photophysical studies of novel 9,10-dihydrophenanthrenes

An efficient metal-free, triflic acid-promoted intramolecular Friedel–Crafts-type carbocyclization of alkenylated biphenyl derivatives is discussed. This method provides an elegant route for the construction of 9,10-dihydrophenanthrenes of biological significance in good to excellent yields. The carbocyclization reaction is likely to proceeds via activation of terminal CC bond of alkenylated biphenyl derivatives followed by subsequent aromatic electrophilic substitution to give desired carbocyclic products. Single crystal X-ray diffraction analysis of compound 10d revealed that the crystals are packed in AB-AB layer packing, where the molecules are aligned in anti-parallel fashion. Notably, all of the synthesized 9,10-dihydrophenanthrenes exhibited blue to greenish yellow fluorescence with λmax = 418–481 nm range. The stokes shift, quantum yield and optical band gap of tricyclic products were computed using their absorption and emission spectra. A significant positive solvatochromic effect was observed for 9,10-dihydrophenanthrene derivative 10l, which is a characteristic of ICT interactions.

Design, Synthesis, and Evaluation of the Selective and Orally Active LSD1 Inhibitor with the Potential of Treating Heart Failure.

LSD1 has become an appealing target for the development of new pharmacologic agents to treat cardiovascular diseases, including heart failure. Herein, we reported the design, synthesis, and structure-activity relationship of a series of TCP-based derivatives targeting LSD1. Docking studies were employed to successfully elucidate the SAR. Particularly, compound 7d, characterized by low toxicity, demonstrated a high affinity for LSD1 at molecular and cellular levels. It also displayed favorable pharmacokinetic properties for oral dosing (e.g., F = 77.61%), effectively alleviating Ang II-induced NRCFs activation in vitro and reducing pathological myocardial remodeling in TAC-induced cardiac remodeling and heart failure in vivo. Additionally, mechanism studies revealed that suppression of myocardial dysfunction by compound 7d is related to LSD1 inhibition-induced TGFβ signaling pathway repressing. In summary, the current report presents compound 7d as a potent LSD1 inhibitor with the potential for further development as a therapeutic agent for pressure overload-related heart failure.

A click-chemistry based strategy for synthesizing coumarin piperazine analogues: Assessment of anti-tubercular, anti-cancer, anti-inflammatory and antioxidant potentials

In this study, a novel series of coumarin piperazine analogues were synthesized using Click chemistry approach. Thus synthesized compounds (8a-j) were evaluated for their pharmacological potentialities. These compounds subjected for evaluation of their anti-tubercular, anti-cancer, anti-inflammatory, and antioxidant properties. Results revealed that analogues 8b, 8d, 8i and 8h are found to be the promising drug-like candidates against Mycobacterium tuberculosis H37Rv strain exhibiting more potent activity than isoniazid with MIC of 2.24, 1.04, 3.72, 5.35 µM respectively. Furthermore, the compound 8d displayed better anti-inflammatory and antioxidant activity with IC50 values of 66.43 µM and 69.14 µM respectively. Molecular docking studies insights into the binding affinities and interactions with a target protein. The in silico ADME profiles supported their pharmacokinetic viability. Predominantly, compound 8d exhibited anticancer activity with IC50 values of 12.42 µM and 26.16 µM with reference to HeLa and MCF-7respectively by inhibiting acetyl-CoA synthetase. These findings highlight more specifically the compound 8d as a potent anti-cancer agent.

Discovery of Cell-Permeable Allosteric Inhibitors of Liver Pyruvate Kinase: Design and Synthesis of Sulfone-Based Urolithins.

Metabolic dysfunction-associated fatty liver disease (MAFLD) presents a significant global health challenge, characterized by the accumulation of liver fat and impacting a considerable portion of the worldwide population. Despite its widespread occurrence, effective treatments for MAFLD are limited. The liver-specific isoform of pyruvate kinase (PKL) has been identified as a promising target for developing MAFLD therapies. Urolithin C, an allosteric inhibitor of PKL, has shown potential in preliminary studies. Expanding upon this groundwork, our study delved into delineating the structure-activity relationship of urolithin C via the synthesis of sulfone-based urolithin analogs. Our results highlight that incorporating a sulfone moiety leads to substantial PKL inhibition, with additional catechol moieties further enhancing this effect. Despite modest improvements in liver cell lines, there was a significant increase in inhibition observed in HepG2 cell lysates. Specifically, compounds 15d, 9d, 15e, 18a, 12d, and 15a displayed promising IC50 values ranging from 4.3 µM to 18.7 µM. Notably, compound 15e not only demonstrated a decrease in PKL activity and triacylglycerol (TAG) content but also showed efficient cellular uptake. These findings position compound 15e as a promising candidate for pharmacological MAFLD treatment, warranting further research and studies.

DFT studies on N-(1-(2-bromobenzoyl)-4-cyano-1H-pyrazol-5-yl)

In this work, molecular descriptors of N-(1-(2-bromobenzoyl)-4-cyano-1H-pyrazol-5-yl) halogenated benzamides (1a-h) have been computed using a quantum chemical technique through DFT. Prior work involved the synthesis of compounds (1a-h) and the assessment of their anticancer activity on breast, colon, and liver tumors: MCF-7, HCT-116, and HepG-2 cell lines respectively. Since 1a, 1b, and 1d showed the most potential anticancer impact, their ability to inhibit EGFRWT was investigated. Based on the biological data, 1b inhibited EGFRWT the most. According to the docking evaluation, an H-bond with the threonine residue was one of the main non-covalent contacts between 1b and the EGFRWT active site residues. PES, MESP, HOMOs, LUMOs, energy band gap, global reactivity indices [electron affinity (A), ionization energies (I), electrophilicity index (ω), nucleophilicity index (ε), chemical potential (μ), electronegativity (χ), hardness (η), and softness (S)], condensed Fukui functions, NBO, and NCIs are the molecular descriptors of 1a-h that were computed using DFT technique. According to the theoretical investigation results, compounds (1a-h) might have anticancer effects; these findings are consistent with the biological findings from our previous research. Compound 1b had the lowest binding energy, according to an assessment of the binding energies between the threonine and the three most active compounds (1a, 1b, and 1d). This is consistent with the outcomes of the docking study and the biological examination of the influence of 1a, 1b, and 1d on EGFRWT.

Design, Synthesis, and Characterization of Novel Thiazolidine-2,4-Dione-Acridine Hybrids as Antitumor Agents.

This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 μM), 13d (IC50 = 4.9 ± 2.9 μM), and 12f·2HCl (IC50 = 4.98 ± 2.9 μM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 μM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 μM), 7f (IC50 = 11.54 ± 2.06 μM), and 7f·2HCl (IC50 = 9.82 ± 1.92 μM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M-1, indicating a good affinity to the BSA protein.

Microwave assisted synthesis, acetylcholinesterase inhibition and molecular docking studies of furo[2,3‐d]pyrido[1,2‐a]pyrimidin‐4‐one derivatives

AbstractA series of phenyl, substituted phenyl and thiophene bearing dihydrofuropyrimidin‐4‐ones (3a‐p) were synthesized by Mn(OAc)3 mediated, microwave irradiated radical cyclizations of 2‐hydroxy‐pyridopyrimidin‐4‐one derivatives (1a‐j) with substituted phenylvinylthiophenes (2a‐c) at 70°C in 2 min. Compounds 3a‐j was obtained between 28% and 66% yields. Molecular structures of 3a‐p were determined by 1H NMR, 13C NMR, 19F NMR, FTIR and HRMS techniques. Inhibitory activity of 3a‐p were evaluated against Acetylcholinesterase (AChE) and inhibition results of these compounds showed that the compounds had good inhibition with IC50 values between 0.52 and 3.77 μM. In addition, molecular docking studies were carried out on the most potent inhibitory compounds 3d (IC50 = 0.64 μM), 3p (IC50 = 0.52 μM) and standart drug Donepezil. The binding energies for 3d, 3p and Donepezil are −9.12, −10.08 and −12.65 Kcal/mol, respectively. Based on these results, it was determined that, compounds 3d and 3p are promising AChE inhibitors.

FeCl3 induced sonochemical heteroarylation: Synthesis of meridianin alkaloid analogues for their in silico/in vitro evaluation against SIRT1

Meridianins A − G, the indole based marine alkaloids have displayed a diverse range of biological properties including anti-cancer / anti-tumour activities. Based on reported correlation between anticancer activities and SIRT1 inhibition, the meridianin alkaloid analogues were explored as possible inhibitors of SIRT1. The FeCl3 mediated regioselective heteroarylation under ultrasound irradiation was employed for the synthesis of this class of N-heterocycles. The methodology involved CC bond forming reaction between 2-amino-4-chloropyrimidine and indole to afford a library of desired compounds in varied yield depending on nature of substituent present on the reactant indole. Indeed the product yield was decreased when the NO2 or OH or two chloro groups were present on the indole ring. The usefulness of the current approach was demonstrated via functionalization of one of the synthesized compound i.e. Meridianin G under ultrasound. All the synthesized compounds were characterized by 1H and 13C NMR and MS spectral data. When docked into the SIRT1 in silico, promising interactions with this protein were noted for some of the meridianin analogues synthesized in addition to their probable selectivity towards SIRT1 over SIRT2. The common interacting residues of SIRT1 were found to be VAL412, PHE413, ILE347, ALA262, ILE411, HIS363, GLN345, ASN346, ILE270, PHE273 and PHE297. Indeed, the top four compounds e.g. 3b, 3c, 3d and 3f participated in H-bond interactions through their indole “NH” and the primary amino group with ASN346, HIS363 and VAL412 of SIRT1. Correlating the findings of in silico studies, these compounds showed promising inhibition of SIRT1 in vitro with IC50 ∼2.9–3.7 µM when 3f emerged as the best active molecule. The SAR (Structure-Activity-Relationship) analysis suggested high to good activities for the NO2, Cl, Br or MeO group at C-5 of indole ring (due to participation of these groups in H-bonding interaction as noted during the in silico docking studies) whereas a free NH moiety of the indole ring was essential for activity. The in silico and in vitro studies along with ADME predictions suggested that compound 3b, 3c, 3d and 3f could be of further pharmacological interest.

Synthesis, Antimicrobial Evaluation, DFT, in Silico-Docking, and ADMET Investigations of Novel Chromene-Based 2,4-Thiazolidinediones.

Three series of thiazolidinedione (TZD) derivatives (5a-f, 7a-f, and 9a-f) were prepared efficiently. Afterward, the synthesized candidates' antibacterial efficacy against both gram-positive and gram-negative bacteria was assessed. Compounds 7c, 7d, and 7f had values comparable to that of ampicillin, a reference antibiotic, whereas compounds 5c, 5d, and 7e exhibited the greatest values (23.0±1.0, 27.7±0.6, and 20.0±1.0, respectively) against gram-positive bacteria (Staphylococcus aureus). The optimal structure of the produced molecules was determined by DFT computing. To assess the binding energy and elucidate the interaction between the potential candidates and different proteins, in silico docking is employed. ADMET analysis to assess the synthesized compounds' toxicity, metabolism, excretion, distribution, and absorption.