Design,synthesis and biological activity of a novel ethylenediamine derivatives as H1 receptor antagonists

In this study, a series of novel ethylenediamine compounds were obtained by structural modification of the lead compounds with thonzylamine, and using the principle of modifying by bioisostere formation and modification with alkyl groups. In vitro assay, the biological activities showed that the target compounds have good properties in inhibiting mast cell degranulation and releasing histamine and β-aminohexidase, such as the compounds 5c, 5g, 5k, 5l and 5o, especially of compound 5k to mast cell degranulation is IC₅₀ = 0.0106 ± 0.001 μmol?L^?1, histamine release was IC₅₀ = 0.0192 ± 0.005 μmol?L^?1 and β-hexosaminidase release was IC₅₀ = 0.0455 ± 0.002 μmol?L^?1 in vitro. At the same time, in vivo biological activities assay results showed that have a good Histamie induce bronchospasm effect with relatively long duration and good protective effect in vivo, among which the protective effect of compound 5k was 79.74 ± 0.30%, compounds 5c, 5g, 5k, 5l and 5o could inhibit the capillary permeability of increasing which were caused by histamine.     

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis,biological activity and structure activity relationship of plasmepsin inhibitors

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C₂ symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K_i, 1.93?±?0.29?µM for Plm II; K_i, 1.99?±?0.05?µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K_i, 0.84?±?0.08?µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC₅₀, 2.27?±?0.95?µM for 10f; IC₅₀, 3.11?±?0.65?µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC₅₀ value of 1.35?±?0.85?µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.     

Design,synthesis and biological evaluation of benzofuran appended benzothiazepine derivatives as inhibitors of butyrylcholinesterase and antimicrobial agents

A series of bezofuran appended 1,5-benzothiazepine compounds 7a–v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC₅₀ value ranging between 1.0?±?0.01 and 72?±?2.8?μM when compared with the standard donepezil (IC₅₀, 2.63?±?0.28?μM). Among the synthesized derivatives, compounds 7l, 7m and 7k exhibited the highest BChE inhibition with IC₅₀ values of 1.0, 1.0 and 1.8?μM, respectively. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 7l with BChE. In addition, docking studies confirmed the results obtained through in vitro experiments and showed that most potent compounds bind to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE active site. The synthesized compounds were also evaluated for their in vitro antibacterial and antifungal activities. The results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms and showed high activity against both gram positive and gram negative bacteria and fungi.     

Design,synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers

Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR^WT; and the most active compounds that showed promising IC₅₀ values against EGFR^WT were tested in vitro for their inhibitory activities against mutant EGFR^T790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC₅₀ values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 µM comparable to that of erlotinib (IC₅₀ ranging from 4.99 ± 0.09 to 13.914 ± 0.36 µM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G₂/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFR^WT and EGFR^T790M.     

Design,synthesis and biological evaluation of novel β-pinene-based thiazole derivatives as potential anticancer agents via mitochondrial-mediated apoptosis pathway

A series of novel β-pinene-based thiazole derivatives were synthesized and characterized by HRMS, ¹H NMR, and ¹³C NMR analyses as potential antineoplastic agents. Derivatives were evaluated for their anticancer activities in vitro, and the data manifested that most target compounds showed potent anti-proliferative activities against three human cancer cell lines. Especially, compound 5g displayed excellent cytotoxic activity against Hela, CT-26, and SMMC-7721 cell lines with IC₅₀ values of 3.48 ± 0.14, 8.84 ± 0.16, and 6.69 ± 0.15 µM, respectively. To determine the underlying mechanism of compound 5g on cell viability, DAPI staining, Annexin-V/PI staining, JC-1 staining, DCFDA staining, and Western blot analysis were performed. Our data showed that compound 5g inhibited cell proliferation by inducing apoptosis and cell cycle arrest of Hela cells at the G0/G1 phase in a dose dependent manner. Further studies revealed that compound 5g enhanced levels of reactive oxygen species (ROS), caused a decrease in mitochondrial membrane potential, increased the release of mitochondrial cytochrome C, and affected the expression of Bax, Bcl-2, caspase-3 and caspase-9. Thus, our findings indicated that compound 5g induced apoptosis in Hela through ROS-mediated mitochondrial dysfunction signaling pathways.     

COX-1/COX-2 inhibition activities and molecular docking study of newly designed and synthesized pyrrolo[3,4-c]pyrrole Mannich bases

In the present paper we describe the biological activity of newly designed and synthesized series of pyrrolo[3,4-c]pyrrole Mannich bases (7a-n). The Mannich bases were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4–c]pyrrole scaffold (6a-c) with secondary amines and an excess of formaldehyde solution in C₂H₅OH. The chemical structures of the compounds were characterized by ¹H NMR, ¹³C NMR, FT-IR, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 7l. All synthesized derivatives were investigated for their potencies to inhibit COX-1 and COX-2 enzymes by colorimetric inhibitor screening assay. In order to analyse the intermolecular interactions between the ligands and cyclooxygenase, experimental data were supported with the results of molecular docking simulations. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2.     

Multifunctional 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase,monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer’s disease

A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC₅₀?=?0.29?±?0.01?μM and 0.46?±?0.02?μM, respectively), MAO-A (IC₅₀?=?8.2?±?0.08?μM and 7.9?±?0.07?μM, respectively) and MAO-B (IC₅₀?=?20.1?±?0.16?μM and 43.8?±?2.0% at 10?μM, respectively) inhibitory activities, moderate self-induced Aβ_1–42 aggregation inhibitory potency (35.4?±?0.42% and 48.0?±?1.53% at 25?μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.     

Design,synthesis and antifungal evaluation of novel pyrazole carboxamides with diarylamines scaffold as potent succinate dehydrogenase inhibitors

Sixteen novel pyrazole carboxamides with diarylamines scaffold were designed, synthesized and characterized in detail via ¹H NMR, ¹³C NMR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani, Fusarium oxysporum, Phytophthora infestans and Fusarium graminearum. Among them, compound 1c exhibited the highest antifungal activities against R. solani in vitro with EC₅₀ value of 0.005?mg/L, superior to the commercially available fungicide fluxapyroxad (EC₅₀?=?0.033?mg/L). And compound 1c (IC₅₀?=?0.034?mg/L) showed higher inhibition abilities against succinate dehydrogenase than fluxapyroxad (IC₅₀?=?0.037?mg/L). This study suggests that compound 1c could be regarded as a potential succinate dehydrogenase inhibitor.     

Sulfur-containing natural hinduchelins derivatives as potential antifungal agents against Rhizoctonia solani

Aryl-oxazole alkaloids are an important class of heterocyclic natural products, and which has been demonstrated to exhibit broad biological functions. During the course of our research for highly active compounds from natural products, the natural hinduchelins A-D with typical aryl-oxazole unit have been synthesized and investigated. So, in order to develop highly potential functional molecules, a series of novel sulfur-containing aryl-oxazole compounds derived from natural hinduchelins was designed and synthesized, and their in vitro fungicidal activities against four common plant pathogenic fungi (oomycetes Phytophthora capsici, ascomycetes Sclerotinia sclerotiorum, deuteromycetes Botrytis cinerea and basidiomycetes Rhizoctonia solani) were evaluated, the results demonstrated that compounds 7b and 7c displayed good selectivity and specificity in vitro against basidiomycetes R. solani. In addition, the in vivo antifungal activities also indicated compounds 7b and 7c can protect the horsebean against infection by R. solani, and the possible mechanism of antifungal action for these compounds has also been investigated.     

Antiplasmodial flavanones and a stilbene from Carpha glomerata

Bioassay-guided fractionation of an extract of Carpha glomerata (Cyperaceae) led to the isolation of seven compounds. Compounds 1 (carphorin A), 3 (carphorin C), 4 (carphorin D), and 5 (carphabene) are new compounds, and compound 2 (8-(3″-hydroxyisoamyl)-naringenin) was isolated for the first time as a natural product. All structures were elucidated based on analyses of their HR-ESIMS and 1D and 2D NMR data. Compounds 1, 2, and 6, which have prenyl or hydroxyprenyl side chains, exhibited antiplasmodial activities with IC₅₀ values of 5.2?±?0.6, 3.4?±?0.4, and 6.7?±?0.8?µM against the drug-resistant Dd2 strain of Plasmodium falciparum. In addition the prenylated stilbene 5 also showed good activity, with IC₅₀ 5.8?±?0.7?µM.     

Design,synthesis, and biological evaluation of pyrazole derivatives containing acetamide bond as potential BRAFV600E inhibitors

With the increasingly acquired resistance, relapse and side effects of known marketed BRAF^V600E inhibitors, it’s significant to design the more effective and novel drugs. In this study, a series of novel pyrazole derivatives containing acetamide bond had been designed and synthesized on the basis of analysis of the endogenous ligands extracted from the known B-Raf co-crystals in the PDB database. Then, the compounds were evaluated for biological activities as potential BRAF^V600E inhibitors. The bioassay results in vitro against three human tumor cell lines revealed that some of the compounds showed very impressed antiproliferative property. Among them, the compound 5r with IC₅₀ values of 0.10?±?0.01?μM against BRAF^V600E and 0.96?±?0.10?μM against A375 cell line, showed the most potent inhibitory effect, compared with the positive-controlled agents vemurafenib (IC₅₀?=?0.04?±?0.004?μM for BRAF^V600E, IC₅₀?=?1.05?±?0.10?μM against A375). Further investigation confirmed that the compound 5r could induce A375 cell apoptosis, induce A375 cell death through changing mitochondrial membrane potential, and result in A375 cell arrest at the G1 phase of the cell cycle. Docking simulations results indicated that the compound 5r could bind tightly at the BRAF^V600E active site. Meanwhile, 3D-QSAR model suggested that these compounds may be potential anticancer inhibitors. Overall, the article provided some new molecular scaffolds for the further BRAF^V600E inhibitors.     

Synthesis and fungicidal activity of novel pyrazole derivatives containing 5-Phenyl-2-Furan

Pyrazole constitutes an important heterocyclic family covering a broad range of synthetic as well as natural products that exhibit numerous chemical, biological, agrochemical and pharmacological properties. In order to explore compounds with good fungicidal activity, a series of new pyrazole derivatives containing 5-phenyl-2-furan were designed and synthesized. In vitro and in vivo fungicidal activities were evaluated and the compound ethyl-1-(5-phenylfuran-2-carbonyl)-5-propyl-1H-pyrazole-3-carboxylate (I8) displayed significant fungicidal activity against various fungi, especially against P. infestans. The structures of the novel pyrazole derivatives were confirmed by ¹H NMR, ¹³C NMR, MS, elemental analysis and X-ray single crystal diffraction. Further study showed that compound I8 might act on the synthesis of cell walls from morphological and ultrastructural studies by SEM and TEM. The results also revealed that compound I8 could block the nutritional transportation leading to cells senescence and death. These results suggested that the novel pyrazole derivatives proved to be promising lead compounds.     

Synthetic indole Mannich bases: Their ability to modulate in vitro cellular immunity

The synthetic indole Mannich bases 1–13 have been investigated for their ability to modulate immune responses measured in vitro. These activities were based on monitoring their affects on T-lymphocyte proliferation, reactive oxygen species (ROS), IL (interleukin)-2, IL-4, and nitric oxide production. Compound 5 was found to be the most potent immunomodulator in this context. Four of the synthesized compounds, 5, 11, 12, and 13, have significant potent inhibitory effects on T-cell proliferation, IL-4, and nitric oxide production. However, none of the thirteen indole compounds exerted any activity against ROS production.     

Iodine mediated pyrazolo-quinoline derivatives as potent anti-proliferative agents

A novel series of substituted pyrazolo-quinoline derivatives 7pa–7qg were synthesized efficiently by using molecular iodine in DMSO and further characterized based on ¹H NMR, ¹³C NMR, IR and HRMS spectral studies. All the synthesized derivatives were screened for their in vitro cytotoxic activity against a panel of five different cancer cell lines such as A549, HeLa, SKNSH, HepG2 and MCF7. The compounds 7pc, 7pd, and 7pj exhibited considerable to promising anti-proliferative activity with IC₅₀ values of 3.76, 3.87 and 3.83?µM against SKNSH cancer cell line. It was revealed that the compounds 7pa and 7pg have shown very close IC₅₀ values of 2.43 and 6.01?µM, against A549 and MCF7 cancer cell lines respectively, which compared to positive control of Doxorubicin. This is the first report on the synthesis and in vitro anti-proliferative evaluation of pyrazolo-quinoline derivatives.     

Synthesis, in vitro α-glucosidase inhibitory activity and docking studies of novel chromone-isatin derivatives

A novel series of chromone-isatin derivatives 6a–6p were designed, synthesized and characterized by ¹H NMR, ¹³C NMR and HRMS. These novel synthetic compounds were evaluated for inhibitory activity against yeast α-glucosidase enzyme. The results of biological test have shown that all tested compounds exhibited excellent to potent inhibitory activity in the range of IC₅₀?=?3.18?±?0.12–16.59?±?0.17?μM as compared to the standard drug acarbose (IC₅₀?=?817.38?±?6.27?μM). Compound 6j (IC₅₀?=?3.18?±?0.12?μM) with a hydroxyl group at the 7-position of chromone and a 4-bromobenzyl group at the N1-positions of isatin, was found to be the most active compound among the series. Furthermore, molecular docking study was performed to help understand binding interactions of the most active analogs with α-glucosidase enzyme. These results indicated that this class of compounds had potential for the development of anti-diabetic agents.     

Synthesis, in vitro and in silico studies of novel potent urease inhibitors: N-[4-({5-[(3-Un/substituted-anilino-3-oxopropyl)sulfanyl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-thiazol-2-yl]benzamides

The present article describes the synthesis, in vitro urease inhibition and in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride (1), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (2) in weak basic aqueous medium followed by hydrazide formation, 4, and cyclization with CS₂ to reach the parent bi-heterocyclic nucleophile, N-{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide (5). Various electrophiles, 8a–l, were synthesized by a two-step process and these were finally coupled with 5 to yield the targeted bi-heterocyclic bi-amide molecules, 9a–l. The structures of the newly synthesized products were corroborated by IR, ¹H NMR, ¹³C NMR, EI-MS and elemental analysis. The in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound 9j, with IC₅₀ value of 2.58?±?0.02?µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC₅₀ value of 21.11?±?0.12?µM. In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds (9a–l) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand 9j exhibited good binding energy value (?7.10?kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that 9j may serve as a novel scaffold for designing more potent urease inhibitors.     

Design,synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives

A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a–j & 8a–j) have been designed and synthesized in excellent yields by Huisgen’s [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, ¹H NMR, ¹³C NMR and HRMS. The newly synthesized compounds 7a–j & 8a–j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56?µg/mL with low cytotoxicity.     

Synthesis and in vitro cytotoxic evaluation of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid

A series of new 1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed and synthesized as potent antitumor agents. Structures of the target molecules were characterized using MS, IR, ¹H NMR, ¹³C NMR and elemental analyses. In the in vitro cytotoxic assay, most compounds showed significant cytotoxic activities against two hepatocarcinoma cells (SMMC-7721 and HepG2) and reduced cytotoxicity against noncancerous human hepatocyte (LO2). Among them, compound 7b exhibited the best cytotoxicity against SMMC-7721 cells (IC₅₀: 0.36 ± 0.13 μM), while 7e was most potent to HepG2 cells (IC₅₀: 0.12 ± 0.03 μM). The cell cycle analysis indicated that compound 7b caused cell cycle arrest of SMMC-7721 cells at G2/M phase. Further, compound 7b also induced the apoptosis of SMMC-7721 cells in Annexin V-APC/7-AAD binding assay.     

Synthesis and bioactivities evaluation of l-pyroglutamic acid analogues from natural product lead

A series of l-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of l-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC₅₀ values of 1.44 and 1.21?μg?mL^?1, which were about seven times that of commercial azoxystrobin (7.85?μg?mL^?1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.     

Synthesis and insecticidal activity in vitro and vivo of novel benzenesulfonyl derivatives based on potent target subunit H of V-ATPase

Two lead compounds with benzenesulfonamide were found through virtual screening based on the 3D structure of the subunit H of V-ATPase in previous study. 74 benzenesulfonyl derivatives were synthesized and their insecticidal activities were evaluated. The derivatives with propargyl substituents exhibit excellent insecticidal activities against Mythimna separata Walker. The LD₅₀ values of compounds A5.7 (28.0?μg·g^?1) and B5.7 (36.4?μg·g^?1) were significantly less than that of Celangulin V (344.0?μg·g^?1). Furthermore, Isothermal Titration Calorimetry (ITC) data indicate there is a strong binding affinity between A5.7 and V-ATPase Subunit H. These results demonstrate that it is a practical way to develop pesticides targeting at H subunit of V-ATPase.