Compounds 4k Research Articles

Click synthesis, antimicrobial, DNA photocleavage and computational studies of oxindole-tethered 1H-1,2,3-triazoles.

Aim: To obtain new hybrids derived from isatin and triazole. Materials & methods: A series of oxindole-1-H-1,2,3-triazole hybrids (4a-l) were synthesized from 3-sulfenylated N-propargylated oxindoles and organic azides employing Cu(I)-catalyzed azide-alkyne cycloaddition. These compounds were evaluated in vitro for antimicrobial activity by the standard serial dilution method and DNA photocleavage activity. Results: Antimicrobial assay revealed that compounds 4l and 4f exhibited promising efficacy against Candida albicans and Rhizopus oryzae, respectively, with aminimum inhibitory concentrationvalue of 0.0008μmol/mL. Compounds 4h and 4k completely degraded plasmid DNA. Further molecular docking of compounds with 1KZN (4j and 4k) and 5TZ1 (4h and 4l) revealed good binding interactions. Conclusion: Results of the current research can help in the development of new antimicrobial agents with high efficacy.

Novel Pyrano[3,2-c]quinoline-1,2,3-triazole Hybrids as Potential Anti-Diabetic Agents: In Vitro α-Glucosidase Inhibition, Kinetic, and Molecular Dynamics Simulation.

In this study, a novel series of pyrano[3,2-c]quinoline-1,2,3-triazole hybrids 8a-o were synthesized and evaluated against the α-glucosidase enzyme. All compounds showed significant in vitro inhibitory activity (IC50 values of 1.19 ± 0.05 to 20.01 ± 0.02 μM) compared to the standard drug acarbose (IC50 = 750.0 μM). Among them, 2-amino-4-(3-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-5-oxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-3-carbonitrile (compound 8k) demonstrated the best inhibitory effect toward α-glucosidase (IC50 = 1.19 ± 0.05 μM) with a competitive pattern of inhibition. Since compound 8k was synthesized as a racemic mixture, molecular docking and dynamics simulations were performed on R- and S-enantiomers of compound 8k. Based on the molecular docking results, both R- and S-enantiomers of compound 8k displayed significant interactions with key residues including catalytic triad (Asp214, Glu276, and Asp349) in the enzyme active site. However, an in silico study indicated that S- and R-enantiomers were inversely located in the enzyme active site. The R-enantiomer formed a more stable complex with a higher binding affinity to the active site of α-glucosidase than that of the S- enantiomer. The benzyl ring in the most stable complex ((R)-compound 8k) was located in the bottom of the binding site and interacted with the enzyme active site, while the pyrano[3,2-c]quinoline moiety occupied the high solvent accessible entrance of the active site. Thus, the synthesized pyrano[3,2-c]quinoline-1,2,3-triazole hybrids seem to be promising scaffolds for the development of novel α-glucosidase inhibitors.

Identification of Potent Inhibitors Targeting EGFR and HER3 for Effective Treatment of Chemoresistance in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were -7.7, -6.3 and -5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC.

Evolution and Discovery of Matrine Derivatives as a New Class of Anti-Hepatic Fibrosis Agents Targeting Ewing Sarcoma Breakpoint Region 1 (EWSR1).

A series of new tricyclic matrinane derivatives were continuously synthesized and evaluated for their inhibitory effects on genes and proteins related to hepatic fibrosis at the cellular level, including collagen type I α1 chain (COL1A1), α smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and matrix metalloprotein 2 (MMP-2). Among them, compound 6k exerted an appealing potency and significantly reduced liver injury and fibrosis in both bile duct ligation (BDL) rats and Mdr2 knockout mice. An activity-based protein profiling (ABPP) assay indicated that 6k might directly bind to Ewing sarcoma breakpoint region 1 (EWSR1) to inhibit its function and affect the expression of downstream liver fibrosis-related genes and thus regulate liver fibrosis. These results provided a potential novel target for the treatment of liver fibrosis and powerful information for the development of tricyclic matrinanes into promising anti-hepatic fibrosis agents.

Synthesis and biological evaluation of coumarine-imidazo[1,2-c][1,2,3]triazoles: PEG-400 mediated one-pot reaction under ultrasonic irradiation

Synthetic chemists have organized easy and effective ways for perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. To investigate the synthesis of fused 1,2,3-triazoles in the presence and absence of ultrasound, the [3 + 2] cycloaddition followed by CN bond formation reaction between 3-(iodoethynyl)-2H-chromen-2-one and substituted 2-chloro-N-phenylacetamides was carried out under relatively optimized conditions. The cancer activity of the synthesized compounds were then tested in vitro against two MCF-7 and A-549 and the majority of the examined compounds 4e-4o showed significant activity, with compounds 4f, 4 g, and 4 h surpassing the standard drug against the A-549 line, and 4 m and 4n excelling it against MCF-7. Later, in vitro EGFR results revealed that compounds 4f (IC50 = 0.420 ± 0.08 μM), 4 g (IC50 = 0.367 ± 0.02 μM), and 4 h (IC50 = 0.453 ± 0.02 μM) were more effective than the conventional medicine Erlotinib (IC50 = 0.460±0.06 μM). In silico investigations of more potent compounds (4f, 4 g, 4 h, 4i, 4k, 4 m, and 4n) and erlotinib on the EGFR protein indicated that all seven compounds had much higher binding energies and inhibition constants than the erlotinib. Finally, the in silico pharmacokinetic profile of compounds 4f, 4 g, 4 h, 4i, 4k, 4 m, and 4n was estimated using SWISS/ADME and pkCSM, where all compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation.

3,4-Dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs act as potential AMPA receptor potentiators with antidepressant activity.

Major depressive disorder is a common psychiatric disorder, with ∼30% of patients suffering from treatment-resistant depression. Based on preclinical studies on ketamine, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation may be a promising therapeutic approach. In this study, we synthesized a series of novel 3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs and analyzed their potential as AMPAR potentiators. Compounds 5aa and 7k exhibited high potentiation with little agonist activity in a high-throughput screen using a calcium influx assay in cultured hippocampal primary neurons. In rats, compound 7k had better pharmacokinetic properties and oral bioavailability (F=67.19%); it also exhibited an acceptable safety profile in vital internal organs based on hematoxylin and eosin staining. We found that 7k produced a rapid antidepressant-like effect in chronic restraint stress-induced mice 1h after intraperitoneal administration. Our study presented a series of novel AMPAR potentiators and identified 7k as a promising drug-like candidate against major depressive disorders.

Design, synthesis and molecular docking of 1,2,4-triazole schiff base hybrids as tubulin, EGFR inhibitors and apoptosis-inducers

The corporate 1,2,4-triazole scaffold was used to synthesize new Schiff base compounds as anticancer agents against several cancer cell lines. Compounds 4d, 4e, and 4k exhibit strong anticancer activity, with IC50 values ranging from 6.78 to 23.03 µM. The inhibitory effects of compounds 4d, 4e, and 4k against EGFR kinase and tubulin were further investigated as they showed significant cytotoxic activity. Compound 4d showed excellent EGFR inhibitory efficacy at an IC50 value of 0.13 µM when compared to lapatinib (IC50 = 0.04 µM). Compound 4k also demonstrated 82.78% inhibition of β-tubulin at 25 μM compared to the untreated control. On the other hand, compound 4d also caused a total cell cycle arrest at the G1/S phase. Furthermore, compound 4d caused 5.28 percent necrosis in the K562 cell line and induced early rather than late apoptosis. A comprehensive molecular docking analysis was carried out to investigate the potential interactions and binding patterns of the three most active compounds, 4d, 4e, and 4k, within the active sites of the targeted EGFR kinase and tubulin polymerization.

Molecular hybridization-based design, PASE three-component synthesis, antiproliferative activity and molecular modelling studies of N,N-dimethylaminophenyl substituted 5H-chromeno[2,3-b]pyridine analogs

A series of N,N-dimethylaminophenyl substituted 5H-chromeno[2,3-b]pyridine derivatives were designed using molecular-hybridization strategy and synthesised using a pot, atom and step economy (PASE) approach. The synthesis involves the one-pot three component reaction of salicyaldehydes, 3-(dimethylamino)phenol and 2-aminopropene-1,1,3-tricarbonitrile catalyzed by triethylamine as a catalyst in ethanol at reflux. This methodology has many beneficial features, including a broad substrate range, easy work up, non-column chromatographic separation, and high product yield. All newly synthesized compounds were screened for their antiproliferative activity towards several human cancer cell lines such as PC3 (prostate), MDA-MB-231 (breast cancer), MIA Paca-2 (pancreatic), HEK293 (hypotriploid) and CHO (Chinese hamster ovary). The SAR identified the compounds 4e and 4k as the most potent analogs in the series, while 4c and 4d demonstrated moderate antitumoral activities. Molecular docking studies revealed that the lead compounds selectively occupy the colchicines binding site of tubulin. Molecular dynamics simulation results supported anticancer efficacy of the synthesized compounds with high molecular stability in binding pocket of heterodimer.

Design, Synthesis, and Antifungal/Antioomycete Activity of Thiohydantoin Analogues Containing Spirocyclic Butenolide.

Novel fungicidal agents were designed based on the combination of two privileged scaffolds, thiohydantoin and spirocyclic butenolide, which are widely found in natural products. The synthesized compounds were characterized by 1H NMR, 13C NMR, and high-resolution electrospray ionisation mass spectrometry. The in vitro antioomycete activity evaluation showed that most of the compounds exhibited excellent inhibitory activities against different developmental stages in the life cycle of pathogenic oomycete Phytophthora capsici. Compound 5j could inhibit the mycelial growth, sporangium production, zoospore release, and cystospore germination significantly with EC50 values of 0.38, 0.25, 0.11, and 0.026 μg/mL, respectively. The in vivo antifungal/antioomycete bioassay results revealed that the series of compounds generally showed outstanding control efficacies against the pathogenic oomycete Pseudoperonospora cubensis, and compounds 5j, 5l, 7j, 7k, and 7l possessed broad-spectrum antifungal activities against the test phytopathogens. The in vivo protective and curative efficacies against P. capsici of the representative compound 5j were excellent, which were better than those of azoxystrobin. More prominently, 5j significantly promoted the biomass accumulation of the root system and reinforced the cell wall by callose deposition. The pronounced upregulation of immune response-related genes indicated that the active oomycete inhibitor 5j also functioned as a plant elicitor. Transmission electron microscopy observation and the enzyme activity test demonstrated that the mechanism of action of 5j was to bind to the pivotal protein, complex III on the respiratory chain, which resulted in a shortage of energy supply. Molecular docking results exhibited that compound 5j appropriately matched with the Qo pocket and had no interaction with the most commonly mutated site Gly-142, which may be of significant benefit in Qo fungicide resistance management. Compound 5j showed great advantages and potential in oomycete control, resistance management, and induction of disease resistance. A further investigation of 5j with a unique structure might have direct implications for the creation of novel oomycete inhibitors against plant-pathogenic oomycetes.

Triple targeting of mutant EGFRL858R/T790M, COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives (6a–p) that triple target the double mutant EGFRL858R/T790M, COX-2, and 15-LOX. Compounds (6e, 6d, 6j, 6m, and 6n) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFRL858R/T790M over wild-type EGFR. Except for 6e and 6n, all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o-treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

SYNTHESIS, CHARACTERIZATION, IN VITRO ANTIMICROBIAL AND ANTIINFLAMMATORY EVALUATIONS OF {5’-(SUBSTITUTED ARYL)-2-FURANYL}-3,4- DIHYDRO-1H-PYRIMIDINE-2-ONE DERIVATIVES

In the present study, a series of 5’-(substituted aryl)-2-furanyl}-3,4-dihydro-1H-pyrimidine-2-ones has been designed and synthesized with Beginelli reaction derivatives carried out from the reaction of ethyl acetoacetate 1 with substituted ureas 2 and substituted aryl furfuraldehydes 3 in presence of acetic acid to yield {5’-(substituted aryl)- 2-furanyl}-3,4-dihydro-1H-pyrimidine-2-ones [4a-k (X=O), 4l-v (X=S)]. The target candidates were confirmed by FTIR, NMR, Mass spectrometry and by elemental analysis. The present exploration also required for in vitro antibacterial activity against Gram-positive strains of bacteria, namely Bacillus cereus (ATCC 11778), Staphylococcus aureus (ATCC 11633), Staphylococcus epidermidis (ATCC 155), Enterococccus faecalis (ATCC 14506) and Gram negative bacterial strains, namely Shigella dysenteriae (ATCC 13313), Escherichia coli (ATCC11303), Klebsiella pneumoniae (ATCC 10031) and Salmonella typhi (MTCC 733). Tested antimicrobial activity revealed that compounds 4k and 4v showed very promising antibacterial activity and were found to be most effective when tested against strains of K. pneumonia, S. aureus, S. typhi, S. epidermidis and E. faecalis, although rest synthesized derivatives also showed significant antibacterial activity. The novel synthesized compounds also exerted remarkable in vitro anti-inflammatory biological activity as reflected by utilization of the percent inhibition of protein denaturation method.

Novel 1,2,3,4-tetrahydroisoquinoline-based Schiff bases as laccase inhibitors: Synthesis and biological activity, 3D-QSAR, and molecular docking studies

Laccase is considered a potential target in the field of agricultural fungicides. To promote the discovery and development of compounds with laccase inhibitory activity, herein, taking reported laccase inhibitor 4-chlorocinnamaldehyde thiosemicarbazide (PMDD-5Y) as the lead compound, two series of 29 novel Schiff-base compounds were designed and synthesized by introducing natural structural unit 1,2,3,4-tetrahydroisoquinoline for the first time. All the synthesized compounds had good antifungal activities against several phytopathogenic fungi in vitro. Among them, compound 4k exhibited prominent biological activities against Valsa mali (EC50 = 5.37 µg/mL), Rhizoctonia solani (EC50 = 3.51 µg/mL), and laccase (IC50 = 0.047 mmol/L), and, thus, could be a promising candidate for a novel chemical fungicide targeting laccase. Furthermore, the structure-activity relationship of the compounds were studied using three-dimensional quantitative structure–activity relationships, molecular docking, and density functional theory calculations. The experimental results preliminarily suggested that the active hydrogen on the nitrogen atom, which acts as a positively charged region, can form key interactions with the laccase target. This may be a key factor in influencing the biological activity.

Design, synthesis, α‐glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole‐carbohydrazide‐phenoxy‐N‐phenylacetamide derivatives

A new series of indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives 7a-l were designed, synthesized, and screened for their α-glucosidase inhibitory abilities and cytotoxic effects. The results obtained in the α-glucosidase inhibition assay indicated that most of the synthesized derivatives displayed good to moderate inhibitory abilities (Ki values ranging from 14.65 ± 2.54 to 37.466 ± 6.46 μM) when compared with the standard drug acarbose (Ki = 42.38 ± 5.73 μM). Among them, 2-mehoxy-phenoxy derivatives 7l and 7h with 4-nitro and 4-chloro substituents on the phenyl ring of the N-phenylacetamide moiety, respectively, displayed the most inhibition effects. The inhibitory mechanism of these compounds was investigated by molecular docking studies. The in vitro cytotoxicity assay showed that only one compound, 2-methoxy-phenoxy derivative 7k with a 4-bromo substituent on the phenyl ring of the N-phenylacetamide moiety, exhibited moderate cytotoxicity against the human non-small-cell lung cancer cell line A549 and the rest of the compounds show almost no cytotoxicity. Further cytotoxic evaluations were also performed on compound 7k. The in silico pharmacokinetic study predicted that the selected compounds 7l and 7h are likely to be orally active.

Abstract 479: Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells

Abstract Pyruvate kinase M2 (PKM2) is a key enzyme involved in the regulation of glycolysis. Although PKM2 is overexpressed in various tumor tissues, its functional role in cancer chemotherapy remains unclear. In this study, we investigated the anticancer activity of novel PKM2 inhibitors in the regulation of cell metabolism and its associated pathways in prostate cancer cells. To evaluate the molecular basis of specific PKM2 inhibitors, the interactions of compounds 3h and 3K with the PKM2 protein were assessed via molecular docking. We found that, compared to compound 3K, compound 3h exhibited a higher binding affinity for PKM2. Moreover, compound 3h significantly inhibited the pyruvate kinase activity and PKM2 expression. Cytotoxicity and colony formation assays revealed the potent anticancer activity of compound 3h against LNCaP cells. Compound 3h significantly increased the apoptotic and autophagic cell death in LNCaP cells. In addition, compound 3h induced AMPK activation along with the inhibition of mTOR/p70S6K pathway. Furthermore, compound 3h significantly inhibited glycolysis and mitochondrial respiration, as determined by analyzing extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) production. Our results revealed that compound 3h caused apoptotic and autophagic cell death by inhibiting cancer cell metabolism in LNCaP cells. Therefore, blocking glycolytic pathways using specific PKM2 inhibitors can be used to target cancer cell metabolism in PKM2-overexpressed prostate cancer cells. Citation Format: Chunxue Jiang, Tian Zheng, HwaYoung Cha, Hyung Sik Kim. Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 479.

Pyrazole derivatives of pyridine and naphthyridine as proapoptotic agents in cervical and breast cancer cells

Cancer is one of the leading causes of death worldwide. The increasing prevalence and resistance to chemotherapy is responsible for driving the search of novel molecules to combat this disease. In search of novel compounds with pro-apoptotic potential, pyrazolo-pyridine and pyrazolo-naphthyridine derivatives were investigated against cervical cancer (HeLa) and breast cancer (MCF-7) cells. The anti-proliferative activity was determined through the MTT assay. Potent compounds were then analyzed for their cytotoxic and apoptotic activity through a lactate dehydrogenase assay and fluorescence microscopy after propidium iodide and DAPI staining. Flow cytometry was used to determine cell cycle arrest in treated cells and pro-apoptotic effect was verified through measurement of mitochondrial membrane potential and activation of caspases. Compounds 5j and 5k were found to be most active against HeLa and MCF-7 cells, respectively. G0/G1 cell cycle arrest was observed in treated cancer cells. Morphological features of apoptosis were also confirmed, and an increased oxidative stress indicated the involvement of reactive oxygen species in apoptosis. The compound-DNA interaction studies demonstrated an intercalative mode of binding and the comet assay confirmed the DNA damaging effects. Finally, potent compounds demonstrated a decrease in mitochondrial membrane potential and increased levels of activated caspase-9 and -3/7 confirmed the induction of apoptosis in treated HeLa and MCF-7 cells. The present work concludes that the active compounds 5j and 5k may be used as lead candidates for the development of lead drug molecules against cervical and breast cancer.

Design, synthesis and evaluation of acridone-2-carbohydrazide derivatives as p-AKT Ser473 kinase inhibitors.

Aim: A series of benzylidene- and phenylethylidene-substituted acridone-2-carbohydrazide derivatives were designed, synthesized and evaluated for their cytotoxicity and response to p-AKT Ser473. Methods: The structures of the synthesized compounds were confirmed by spectroscopic techniques and evaluated for AKT enzyme inhibition activities. Molecular docking and in silico absorption, distribution, metabolism, elimination and toxicity studies were also performed. Results: Compounds 8k, 8v and 9h demonstrated good cytotoxicity against breast cancer cell lines. Especially, compounds 8v and 9h exhibited remarkable inhibition, with IC50 values of 1.75 and 2.40 μM, respectively. These compounds inhibited p-AKT Ser473 more specifically than total AKT in a dose-dependent manner. Moreover, they caused G0/G1-phase cell cycle arrest and cell apoptosis. Conclusion: This study identified compound 8v as a potent p-AKT Ser473 inhibitor.

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of > 20 µM < 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 > 125 µM).

Catalyst-free synthesis of imidazo[5,1-b]quinazolines and their antimicrobial activity

In this study, imidazo[5,1-b]quinazoline derivatives 4(a–t) were synthesized via a three-component reaction of 5-aminoimidazole-4-carbonitrile, 1,3-cyclohexanedione derivatives and various aromatic aldehydes by employing glacial acetic acid as a reaction medium. This catalyst-free approach affords mild reaction conditions and has operational simplicity resulting in excellent yield in a shorter reaction time without any chromatographic separation method. All the synthesized compounds were screened for their antimicrobial activity against the pathogenic strains. The compounds 4c and 4e exhibit a more promising (MIC = 25 µg/mL) against S. pyogenes and E. coli bacterial strains than the standard drug ampicillin (MIC = 100 µg/mL) and chloramphenicol (MIC = 50 µg/mL) respectively. Compounds 4c, 4h, 4k and 4r showed pronounced antifungal activity (MIC = 250 µg/mL) against C. albicans compared to the standard drug griseofulvin (MIC = 500 µg/mL). Further, compound 4k was found to have good antimalarial inhibition (IC50 = 0.28 µg/mL) against P. falciparum, similar to the standard drug quinine (IC50 = 0.27 µg/mL). Binding interactions of 4e in the active site of E. coli DNA gyrase (PDB ID: 1KZN) showed good interaction with the target protein. Potent antimicrobial active compounds 4c, 4e and 4k showed drug-likeness with a good ADME profile.

Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis.

A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 μg/mL, respectively, whereas the LC50 value of MA was 659.34 μg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 μg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.

Design, synthesis and in vitro antitubercular evaluation of novel 7-methoxy pyrrolo[1,2-a]quinoline analogues as CYP 121 inhibitors

A novel series of pyrrolo[1,2-a]quinoline analogues (4a-n) was designed via a heterocyclic fusion approach for their antitubercular evaluation. The targeted compounds were synthesized by reacting 6-methoxy quinoline with different substituted phenacyl bromides, to get quinolinium ylide intermediates (2a-i), which have further undergone [3+2] cycloaddition with electron-deficient acetylenes to furnish novel 7-methoxy pyrrolo[1,2-a]quinoline derivatives (4a-n). All these newly synthesized intermediate products and final compounds have been characterized by spectroscopic techniques such as 1H NMR, 13C NMR, HRMS, and FT-IR. The intermediate ylides and final pyrrolo[1,2-a]quinoline analogues were evaluated for their antitubercular potential against the Mtb H37Rv strain (ATCC 27294). All the tested compounds exhibited antitubercular activity with the MIC99 in the range of 25–50 µM (10.4–25.7 µg/mL), compared to the standard drug Isoniazid (0.195 µM=0.026 µg/mL). An in silico molecular docking study revealed the strong binding affinity of target compounds with the enzyme Mtb CYP 121. The pharmacokinetic properties and toxicity predictions indicate overall drug-likeness for synthesized compounds. In this study, the compounds 4i, 4j, and 4k displayed considerable anti-TB activity against Mtb H37Rv with MIC99 values of 25 µM (10.43, 10.54, and 11.65 µg/mL respectively). CC50 of the test compounds were determined by cell viability assay using THP-1 macrophages. The compounds having methoxy and halogen substitution at the para position of the benzoyl fragment of designed molecules exhibited the best activity among the series.