Fluorinated indeno-quinoxaline bearing thiazole moieties as hypoglycaemic agents targeting α-amylase, and α-glucosidase: synthesis, molecular docking, and ADMET studies.

Inhibition of α-glucosidase and α-amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2-b] quinoxalines-carrying thiazole hybrids 1-17 were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds 4, 6, 8, and 16 were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against α-glucosidase and α-amylase enzymes in vitro. The four hybrids 4, 6, 8, and 16 represented moderate to potent activity with IC50 values 0.982 ± 0.04, to 10.19 ± 0.21 for α-glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 µM for α-amylase inhibition when compared to the standard medication acarbose with IC50=0.316 ± 0.02 µM for α-glucosidase inhibition and 31.56 ± 1.33 µM for α-amylase inhibition. Docking studies as well as in silico ADMT were done.

Erratum to "Facile synthesis and in vitro anticancer evaluation of a new series of tetrahydroquinoline" [Heliyon 7(10) (October 2021) e08117].

[This corrects the article DOI: 10.1016/j.heliyon.2021.e08117.].

Interception of Epoxide ring to quorum sensing system in Enterococcus faecalis and Staphylococcus aureus.

Quorum sensing inhibitor (QSI) has been attracting attention as anti-virulence agent which disarms pathogens of their virulence rather than killing them. QSI marking cyclic peptide-mediated QS in Gram-positive bacteria is an effective tool to overcome the crisis of antibiotic-dependent chemotherapy due to the emergence of drug resistance strain, e.g., methicillin resistant Staphylococcus aureus (MRSA) and Vancomycin resistant Enterococci (VRE). From a semi-large-scale screening thus far carried out, two Epoxide compounds, Ambuic acid and Synerazol, have been found to efficiently block agr and fsr QS systems, suggesting that the Epoxide group is involved in the mode of action of these QSIs. To address this notion, known natural Epoxide compounds, Cerulenin and Fosfomycin were examined for QSI activity for the agr and fsr systems in addition to in silico and SAR studies. As a result, most of investigated Epoxide containing antibiotics correlatively interfere with QSI activity for the agr and fsr systems under sublethal concentrations.

Development of new spiro[1,3]dithiine-4,11'-indeno[1,2-b]quinoxaline derivatives as S. aureus Sortase A inhibitors and radiosterilization with molecular modeling simulation.

Multi-drug resistant microbes have become a severe threat to human health and arise a worldwide concern. A total of fifteen spiro-1,3-dithiinoindenoquinoxaline derivatives 2-7 were synthesized and evaluated for their biological activities against five standard and MDRB pathogens. The MIC and MBC/MFC for the most active derivatives were determined in vitro via broth microdilution assay. These derivatives showed significant activity against the tested strains with microbicidal behavior, with compound 4b as the most active compound (MIC range between 0.06 and 0.25 µg/mL for bacteria strains and MIC = 0.25 µg/mL for C. albicans). The most active spiro-1,3-dithiinoindenoquinoxaline derivatives were able to inhibit the activity of SrtA with IC50 values ranging from 22.15 ± 0.4 µM to 37.12 ± 1.4 µM. In addition, the active spiro-1,3-dithiinoindenoquinoxaline attenuated the in vitro virulence-related phenotype of SrtA by weakening the adherence of S. aureus to fibrinogen and reducing the biofilm formation. Surprisingly, compound 4b revealed potent SrtA inhibitory activity with IC50 = 22.15 µM, inhibiting the adhesion of S. aureus with 39.22 ± 0.15 % compared with untreated 9.43 ± 1.52 %, and showed a reduction in the biofilm biomass of S. aureus with 32.27 ± 0.52 %. We further investigated the effect of gamma radiation as a sterilization method on the microbial load and found that a dose of 5 kGy was sufficient to eradicate the microbial load. The quantum chemical studies exhibited that the tested derivatives have a small energy band gap (ΔE = -2.95 to -3.61 eV) and therefore exert potent bioactivity by interacting with receptors more stabilizing.

The effect of novel synthetic semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles on the apoptotic markers, VEGFR-2, and cell cycle of myeloid leukemia.

Vascular Endothelial Growth Factor II (VEGFR-2) has been proved as a rational target in cancer therapy. Although currently prescribed VEGFR-2 inhibitors are showing potent antitumor activity, they are often causing serious unwanted effects, restricting their extensive use as chemotherapeutics. Herein, after analyzing the structures of the effective VEGFR-2 inhibitor molecules, we report the synthesis of a new set of semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles with expected potency of inhibiting the VEGFR-2 signaling. The design of new compounds considered maintaining the essential pharmacophoric features of sorafenib for effective binding with the receptor target. All compounds have been evaluated for their growth inhibition effect against a panel of sixty cancer cells at the National Cancer Institute. Leukemia cancer cells, especially HL-60 and SR, were shown to be the most sensitive to the cytotoxic effect of new compounds. Thiosemicarbazones 21, 26, and 30 exhibited the best activity against almost all tested cancer cells. Therefore, a set of subsequent in vitro biological evaluations has been performed to understand the mechanistic effect of these compounds further. They inhibited the VEGFR-2 with IC50 values of 0.128, 0.413, and 0.067 µM respectively compared with 0.048 µM of Sorafenib. The probable mechanistic effect of 30 has been further evaluated on a number of apoptotic and antiapoptotic markers including BAX, BCL2, caspase-3, and caspase-9. Results revealed the potential of the thiosemicarbazone-linked triazole 30 to induce both the early and the late apoptosis, elevate BAX/BCL2 ratio, induce caspase-3 & caspase-9, and arrest the HL-60 cell cycle at the G2/M and G0-G1 phases. Molecular docking of new semicarbazones and thiosemicarbazones into the proposed biological target receptor has also been performed. Results of docking studies proved the potential of new semicarbazone- and thiosemicarbazone-linked 1,2,3-triazoles to effectively bind with crucial residues of the VEGFR-2 binding pocket.

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein.

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2a-e and isatin derivatives 1a-c to synthesize spiro-oxindoles 3a-d, 4a-e, and 5a-e. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5'-pyrido[2,3-d:6,5-d']dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids.

Apoptosis induction, PARP-1 inhibition, and cell cycle analysis of leukemia cancer cells treated with novel synthetic 1,2,3-triazole-chalcone conjugates.

Leukemia is a life-threatening nonepithelial malignant disorder that is characterized by uncontrolled growth of the hematopoietic cells. To date, there are still unmet needs for effective and less toxic medication for the management of this malignant tumor. Here, we report the synthesis of a new set of suggested anticancer molecules by joining the 1,2,3-triazole and chalcone privileged fragments in one scaffold to develop novel candidates in leukemia therapy. All the synthesized compounds have been screened for their cytotoxicity effect against a panel of 60 cancer cell lines at the National Cancer Institute. The leukemia cancer cells were found to be the most sensitive toward the effect of new molecules. A subsequent set of in vitro biological evaluation studies has been conducted on the most promising derivatives to identify their effect on such a cancer type. Four derivatives (11b, 11e, 11h, and 11j) showed excellent anticancer activity in the RPMI-8226 cells with IC50 values at low micromolar concentrations. Among these compounds, 11e was the most effective with an IC50 value of 3.17 µM (32-folds stronger than Staurosporine). The potential mechanistic effect of the latter has been further studied through the investigation of its potential effect on the cell cycle, PARP-1, and certain apoptotic and anti-apoptotic markers in the RPMI-8226 cells. Results of those studies revealed the potential of 11e to induce apoptosis through the upregulation of BAX, caspase-3, and caspase-9, and to arrest the cell cycle at the S phase.

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study.

Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes' expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and its ortholog fsr quorum sensing systems, respectively. In the present study, we screened a set of 54 actinomycetales secondary metabolites as novel anti-virulence compounds targeting quorum sensing system of the Gram-positive bacteria. The results indicated that four compounds, Phenalinolactones A-D, BU-4664LMe, 4,5-dehydrogeldamycin, and Questinomycin A, potentially inhibit the agr quorum sensing system and hemolytic activity of S. aureus. On the other hand, Decatromicin A and B, Okilactomycin, Rishirilide A, Abyssomicin I, and Rebeccamycin selectively blocked the fsr quorum sensing system and the gelatinase production in E. faecalis at sub-lethal concentrations. Interestingly, Synerazol uniquely showed the capability to inhibit both fsr and agr quorum sensing systems. Further, in silico molecular docking studies were performed which provided closer insights into the mode of action of these compounds and proposed that the inhibitory activity of these compounds could be attributed to their potential ability to bind to the ATP-active site of S. aureus AgrA. Taken together, our study highlights the potential of actinomycetales secondary metabolites with diverse structures as anti-virulence quorum sensing inhibitors.

Upregulation of BAX and caspase-3, as well as downregulation of Bcl-2 during treatment with indeno[1,2-b]quinoxalin derivatives, mediated apoptosis in human cancer cells.

Cancer is the world's foremost cause of death. There are over 100 different forms of cancer. Cancers are frequently named after the organs or tissues in which they develop. As a part of our aim to develop promising anticancer agents, a series of new indeno[1,2-b]quinoxaline derivatives were synthesized. All of the synthesized compounds were tested for anticancer activity in vitro in three human cancer cell lines: the HCT-116 colon cancer cell line, the HepG-2 liver cancer cell line, and the MCF-7 breast cancer cell line. Among the tested derivatives, 2, 3, 5, 12, 21, and 22 showed exceptional antiproliferative activities against the three tested cell lines compared to the reference standard imatinib. These compounds were, therefore, selected for further investigations. Evaluation of their cytotoxicity against a normal human cell line (WI-38) was performed, to ensure their safety and selectivity (IC50 > 92 µM). Then, induction of apoptosis by the most active compounds was found to be accomplished by downregulation of Bcl-2 and upregulation of BAX and caspase-3. After that, the most promising apoptotic compound that increases the caspase-3 and BAX expression and downregulates Bcl-2 activity (3) was assessed for its impact on the cell cycle distribution in HepG-2 cells: The most potent derivative (3) induced cell cycle arrest at the G2/M phase. Finally, in silico evaluation of the ADME properties indicated that compound 3 is orally bioavailable and can be readily synthesized on a large scale.

In vitro antimicrobial evaluation and in silico studies of coumarin derivatives tagged with pyrano-pyridine and pyrano-pyrimidine moieties as DNA gyrase inhibitors.

Several coumarin-containing substitute nitrogen heterocycles have recently received considerable importance due to their diverse pharmacological properties. One-pot and rapid synthesis of coumarin derivatives was achieved via reactions of acetyl-coumarin with p-chloro-benzaldehyde and malononitrile to provide compound 2-containing cyano-amine using conventional heating. Compound 2 was condensed with different carbon electrophiles triethyl orthoformate, phenyl isocyanate, carbon disulfide, benzoyl chloride, and acetyl chloride that afforded the corresponding chromene derivatives 3-17. All the newly synthesized compounds were characterized by elemental and spectroscopic evidences. All of the synthesized compounds were tested for antimicrobial activity against S. Pneumoniae, S. Epidermidis, S. Aureus, and E. coli as Gram + ve Bacteria, K. Pneumoniae, S. Paratyphi as Gram -ve Bacteria, P. Italicum, A. Fumigatus representative for Fungi. The preliminary screening results showed that most of the compounds had moderate to high activity against all tested organisms. The most potent four compounds were subjected to further investigation against E. Coli DNA gyrase and topoisomerase IV inhibitory activity, and the results showed that all of these derivatives inhibit DNA gyrase and thus cell division. Also, in silico studies were done for the most active compounds which showed good results.

Facile synthesis and in vitro anticancer evaluation of a new series of tetrahydroquinoline.

Tetrahydroquinoline (THQ) is an important structure for synthesizing multiple biologically active derivatives. Thus, we developed new quinoline derivatives and investigated them as anticancer agents. First, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and other techniques were used to confirm the structure of synthesized compounds. Then, they were assessed in vitro against three human cancer cell lines. Consequently, four compounds, 10, 13, 15, and 16, were identified as promising anticancer agents with pyrazolo quinoline derivative (15) exhibiting the highest potential IC50 and a strong apoptotic effect on three cell lines.

In vivo screening and toxicity studies of indolinone incorporated thiosemicarbazone, thiazole and piperidinosulfonyl moieties as anticonvulsant agents.

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA.

Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC50 values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12-0.25 µM) compared to Vancomycin (1-2 µM), and MBC values ranging from (0.5-1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation.

Novel structural hybrids of quinoline and thiazole moieties: Synthesis and evaluation of antibacterial and antifungal activities with molecular modeling studies.

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of quinolines bearing a thiazole moiety were synthesized using thiosemicarbazones 2a-f. Cyclization of 2a-f with ethyl chloroacetate, ethyl 2-chloropropanoate or chloroacetone afforded the corresponding thiazoles 3-5. The antimicrobial activity of the new quinoline derivatives was evaluated. The most of tested compounds revealed potent both of the antibacterial and antifungal activities. Fourfold potency of amphotericin B for the inhibition the growth of the A. fumigatus was displayed by ccompound 5e. The latter compound displayed twofold potency of gentamycin for inhibition the growth of N. gonorrhoeae. Moreover, this compound showed equipotent potency of references drugs for inhibition of the growth of S. flexneri, S. pyogenes, P. vulgaris, A. clavatus, G. candidum and P. marneffei. So, quinolines bearing a thiazole moiety can be suggested as interesting scaffolds for the development both of the novel antibacterial and antifungal agents. Some new derivatives were studied as peptide deformylase enzyme inhibitors. Thiazolidin-4-one derivative 3d and 2,3-dihydrothiazole derivative 5c had shown good PDF inhibition activity, which had been supported by the docking results with highest binding affinity and lowest docking energy score. These results suggested that the most potent compounds might be possible agents as novel bacterial PDF inhibitor.

In vivo and in vitro anti-inflammatory, antipyretic and ulcerogenic activities of pyridone and chromenopyridone derivatives, physicochemical and pharmacokinetic studies.

Throughout this study, we present the victorious synthesis of a novel class of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety through a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with cyanoacetamide, acetylacetone or ethyl acetoacetate, and their corresponding aldehydes. In addition, the chromene moiety was introduced into the pyridine skeleton through the cyclization of the cyanoacetamide 2 with salicylaldehyde, followed by treatment with malononitrile, ethyl cyanoacetate, and cyanoacetamide, in order to improve their biological behaviour. Due to their anti-inflammatory, ulcerogenic, and antipyretic characters, the target molecules have undergone in-vitro and in-vivo examination, that display promising results. Moreover, in order to predict the physicochemical and ADME traits of all synthesized compounds and standard reference drugs, paracetamol and phenylbutazone, the in-silico prediction methodology was provided.

In vitro cytotoxic activity of thiazole-indenoquinoxaline hybrids as apoptotic agents, design, synthesis, physicochemical and pharmacokinetic studies.

In this study, anti-proliferative effects of twenty-seven indeno[1,2-b]quinoxalin-11-one derivatives were investigated in three human cancer cell lines, namely: the colon cancer cell line HCT-116, the liver cancer cell line HepG-2, and the breast cancer cell line MCF-7. Among them, 5, 6, 13, 14a, b and 15d-f derivatives displayed excellent anti-proliferative activities against the three tested cell lines compared to the reference standard Imatinib. Therefore, they were selected for further studies. First, to ensure the safety of our hits, investigation of the IC50 values on normal human cells (WI-38) was executed indicating that, they are highly selective (IC50 > 107 µM) in their cytotoxic effect. Second, the induction of apoptosis by these active compounds was achieved by down-regulation of Bcl-2 and up-regulation of BAX and caspase-3. Further investigations have shown that 14b and 15f, the most potent derivatives, induced cell cycle arrest at G2/M phase. Moreover, in silico evaluation of ADME properties indicated that all the potent compounds are orally bioavailable with no permeation to the blood brain barrier.

Antimicrobial evaluation of thiadiazino and thiazolo quinoxaline hybrids as potential DNA gyrase inhibitors; design, synthesis, characterization and morphological studies.

A series of thiadiazino[5,6-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives was designed and synthetized from the reaction of 2,3-dichloro-6-(morpholinosulfonyl)quinoxaline (2) with thiosemicarbazide or thiocarbohydrazide and thiourea derivatives to give nineteen quinoxaline derivatives 3-16. All the synthesized compounds were evaluated for in vitro antimicrobial potential against various bacteria and fungi strains that showed considerable antimicrobial activity against tested microorganisms. The most potent compounds 2, 7, 9, 10, 12 and 13c were exhibited bactericidal activity, in addition to fungistatic activity by dead live assay. Moreover, these compounds showed a significant result against all multi-drug resistance (MDRB) used especially compound 13c that displayed the best results with MICs of MDRB (1.95, 3.9, 2.6, 3.9 µg/mL) for stains used in this study, compared with Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL). Also, cytotoxicity on normal cell (Vero cells ATCC CCL-81) by MTT assay was performed with lower toxicity results. Additionally, morphological studies, immunostimulatory potency and DNA gyrase inhibition assay of most active compounds was done. A molecular docking study has also been carried out to support the effective binding of the most promising compounds at the active site of the target enzyme S. aureus DNA gyrase (2XCT).

Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents.

3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver carcinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64-7.73 µg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated.

Quinoline derivatives bearing pyrazole moiety: Synthesis and biological evaluation as possible antibacterial and antifungal agents.

In an attempt for development of new antimicrobial agents, three series of quinoline derivatives bearing pyrazole moiety have been synthesized. The first series was synthesized through the synthesis of 4-(quinolin-2-yloxy)benzaldehyde and 4-(quinolin-2-yloxy)acetophenone and then treatment with ketone or aldehyde derivatives to afford the corresponding chalcones. Cyclization of the latter chalcones with hydrazine derivatives led to the formation of new pyrazoline derivatives. The second series was synthesized via the synthesis of 2-hydrazinylquinoline and then treatment with formylpyrazoles to afford the corresponding hydrazonyl pyrazole derivatives. The third series was synthesized through the treatment of 2-hydrazinylquinoline with ethoxyethylidene, dithioacetal and arylidene derivatives to afford the corresponding pyrazole derivatives. The synthesized compounds were evaluated for their expected antibacterial and antifungal activities; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Pyrazole derivative 13b showed better results when compared with the reference drugs as revealed from their MIC values (0.12-0.98 µg/mL). The pyrazole derivative 13b showed fourfold potency of gentamycin in inhibiting the growth of S. flexneri (MIC 0.12 µg/mL). Also, compound 13b showed fourfold potency of amphotericin B in inhibiting the growth of A. clavatus (MIC 0.49 µg/mL) and C. albicans (MIC 0.12 µg/mL), respectively. The same compound showed twofold potency of gentamycin in inhibiting the growth of P. vulgaris (MIC 0.98 µg/mL), equipotent to the ampicillin and amphotericin B in inhibiting the growth of S. epidermidis (MIC 0.49 µg/mL), A. fumigatus (MIC 0.98 µg/mL), respectively. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antibacterial and antifungal agents.

One pot synthesis, antimicrobial and antioxidant activities of fused uracils: pyrimidodiazepines, lumazines, triazolouracil and xanthines.

BACKGROUND: Uracil derivatives have a great attraction because they play an important role in pharmacological activities. Pyrimidodiazepines, lumazines, triazolopyrimidines and xanthines have significant wide spectrum activities including anticancer, antiviral as well as antimicrobial activities. RESULTS: A newly synthesized compounds pyrimido[4,5-b][1, 4]diazepines 5a-e, 6a-d, lumazines 7a-d, triazolo[4,5-d]pyrimidine 8 and xanthines 9, 10 was prepared in a good yields. The antimicrobial and antioxidant activities of compounds 5a, 5b, 6a, 6d and 8 exhibited a wide range activity against the pathogenic tested microbes (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, and Saccharomyces cerevisiae). Compound 8 showed activity against the fungus Aspergillus niger. The highest antioxidant activity was noticed for compound 5a. CONCLUSIONS: A series of novel pyrimido[4,5-b][1, 4]diazepines 5a-e, 6a-d, lumazines 7a-d, triazolo[4,5-d]pyrimidine 8 and xanthines 9, 10 was prepared from 5,6-diamino-1-(2-chlorobenzyl)uracil 3 in good yields. Compounds 5a-e, 6a-d were prepared by sequential manipulation of 3 with α,ß-unsaturated ketones. Lumazines 7a-d were obtained from 3 by treatment with phenacyl bromides in the presence of TEA. Compound 8 was prepared by treatment of 3 with HNO2, while xanthines 9, 10 were obtained from 3 by consecutive acetylation then intramolecular cyclodehydration or heating with malononitrile under solvent-free condition. The antimicrobial and antioxidant activity of this series was evaluated in vitro and they showed either weak or moderate activities. Graphical abstract Several pyrimido[4,5-b][1,4]diazepines, lumazines, triazolo-, and imidazolopyrimidines were synthesized from the starting compound 4,5-diaminouracils. The newly synthesized compounds were screened for both antimicrobial and antioxidant activities.