Synthesis and Evaluation of Novel Marine Bromopyrrole Alkaloid‐Based Derivatives as Potential Antidepressant Agents

Herein, we report synthesis and screening of a series of twenty derivatives of bromopyrrole alkaloids with aroyl hydrazone feature for antidepressant activity by forced swim test (FST), tail suspension test (TST), and actophotometer method. The molecules were further evaluated for in vitro human MAO's inhibitory activities. The tested compounds exhibited moderate to good antidepressant activity compared with standard fluoxetine. Among these, most promising antidepressant derivatives 5b (%DID = 60.48), 5e (%DID = 59), and 5j (%DID = 74.86) reduced immobility duration of 50–70% at 30 mg/kg dose levels in FST. Further, derivative 5b , 5e, and 5j displayed good antidepressant activity with %DID value of 47.50, 46.62, and 52.49, respectively, in TST compared with standard fluoxetine (66.56% DID). Compound 5b showed high in vitro MAO‐A potency and selectivity (K_i MAO‐A (μm ) = 2.4 ± 0.99, SI = 0.06) with promising pharmacological activity recognizing its potential as antidepressant lead candidate for further drug development. Study revealed that the presence of halogen atoms such as chlorine and fluorine at ortho‐ and/or para‐position of phenyl ring and N‐alkylation of pyrrole core is favored features for antidepressant activity.     

Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents

A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke.     

Synthesis,Biological Evaluation,and Docking of Dihydropyrazole Sulfonamide Containing 2‐hydroxyphenyl Moiety: A Series of Novel MMP‐2 Inhibitors

In this study, we synthesized a series of dihydropyrazole sulfonamide derivatives containing 2‐hydroxyphenyl moiety as antitumor agents to target the matrix metalloproteinase‐2 (MMP‐2). All of the synthesized compounds were examined by bioactivity assays, in which compound 4c turned out as a potential antagonist of MMP‐2 along with potent anticancer activity against four tumor cell lines. Structure–activity relationship analysis was also performed to examine how structural changes impacted the bioactivity. Suggested to be caused by the induction of apoptosis, the antitumor mechanism of 4c was further confirmed by PI combining with annexin V‐FITC staining assay using flow cytometry analysis. These new findings along with molecular docking observations suggested that compound 4c could be developed as a potential anticancer agent.     

Synthesis and Biological Evaluation of Novel FtsZ‐targeted 3‐arylalkoxy‐2,6‐difluorobenzamides as Potential Antimicrobial Agents

Novel series of 3‐O‐arylalkylbenzamide and 3‐O‐arylalkyl‐2,6‐difluorobenzamide derivatives were synthesized and evaluated for their on‐target activity and antibacterial activity. The results indicated that the 3‐O‐arylalkyl‐2,6‐difluorobenzamide derivatives possessed much better on‐target activity and antibacterial activity than the 3‐O‐arylalkylbenzamide derivatives. Among them, 3‐O‐chlorobenzyl derivative 36 was the most effective in antibacterial activity (0.5, 4, and 8 μg/mL) against Bacillus subtilis ATCC9372, methicillin‐resistant Staphylococcus aureus ATCC29213, and penicillin‐resistant Staphylococcus aureus PR, while 3‐O‐methylbenzyl derivative 41 only exhibited the most potent activity (2 μg/mL) against Staphylococcus aureus ATCC25923.     

Design,Synthesis and Bioevaluation of Novel N‐Substituted‐3,5‐Bis(Arylidene)‐4‐piperidone Derivatives as Cytotoxic and Antitumor Agents with Fluorescent Properties

Ten new N‐substituted‐3,5‐bis(arylidene)‐4‐piperidone derivatives (series 1 and 2 ) were synthesized and subsequently evaluated against human carcinoma cell lines SW1990, MIA PaCa‐2, PG‐BE1, NCI‐H460, and SK‐BR‐3 for cytotoxic activity by the CCK‐8 method, and their fluorescent properties were investigated as well. The compounds were confirmed to display greater cytotoxic activity to the neoplastic cells, and approximately 50% of the IC₅₀ values were lower than 5 μm . In particular, compounds 1a , 1c , 1d, and 1e bearing 3‐bromophenyl groups were revealed as the most active antitumor drug candidates and had the average IC₅₀ values of 1.94, 1.11, 1.16, and 0.817 μm , respectively. Furthermore, their fluorescent properties were interesting and might contribute to the visualization of their distribution in tumor cells. Some possible reasons for the disparity between cytotoxic activity and fluorescent properties in the two series of compounds were explored. This study revealed high potential of these molecules for further development as fluorescent cytotoxic and antitumor agents.     

Synthesis and In‐vitro Activity of 4′‐Modified Analogues of ddA as Potent Anti‐HIV Agents

This paper reports the synthesis of novel 4′‐hydrophobic pocket deoxythreosyl C‐nucleosides. The key threose‐like intermediates 9 and 14 were constructed from acyclic ketone derivatives, respectively. The antiviral activities of the synthesized compounds against the HIV‐1, HSV‐1, HSV‐2, and HCMV viruses were evaluated. The 9‐deaza‐adenine derivatives 10 and 20 showed good anti‐HIV activity without exhibiting significant cytotoxicity.     

Synthesis of new pyrazolo[3,4‐d]pyrimidine derivatives and evaluation of their anti‐inflammatory and anticancer activities

This study reports the synthesis of two series of new purine bioisosteres comprising a pyrazolo[3,4‐d]pyrimidine scaffold linked to piperazine moiety through different amide linkages. The newly synthesized compounds were evaluated for anticancer activity against four cell lines (MDA‐MB‐231, MCF‐7, SF‐268, B16F‐10) and cyclooxygenase (COX‐2) protein expression inhibition in lipopolysaccharide (LPS)‐activated rat monocytes. The results revealed that most of the synthesized compounds showed moderate‐to‐high cytotoxic activity against at least one cell line, with compound 10b being the most active against all used cell lines (IC₅₀ values 5.5–11 μg/ml) comparable to cisplatin. In addition, six of these compounds ( 7b, 10a–d, and 12c ) demonstrated inhibition of LPS‐induced COX‐2 protein expression at low concentration (25 μg/ml) as compared to the control non‐stimulated cells and showed a COX‐2 selectivity index range comparable to diclofenac sodium. The overall results indicate that many of these pyrazolopyrimidine derivatives possess in vitro anti‐inflammatory and anticancer activities at varying doses, and the most active compounds will be subjected to in vivo pharmacological evaluation.     

Synthesis of Novel Substituted Thiourea and Benzimidazole Derivatives Containing a Pyrazolone Ring as Anti‐Inflammatory Agents

Two series of new 1‐(alkyl/aryl)‐3‐{2‐[(5‐oxo‐4,5‐dihydro‐1H‐pyrazol‐3‐yl)amino]phenyl}thioureas 2a – h and 5‐[2‐(substituted amino)‐1H‐benzimidazol‐1‐yl]‐4H‐pyrazol‐3‐ols 3a – i were designed and synthesized as anti‐inflammatory agents. The cyclooxygenase inhibitory activity of the newly synthesized compounds was investigated. All the compounds showed non‐selective inhibition of COX‐1 and COX‐2 enzymes which was consistent with their docking results. Compounds 2c , 2f , 2g , 3b , and 3g that showed the highest COX‐2 inhibitory activity were selected for further in vivo testing as anti‐inflammatory agents using diclofenac as a reference drug. Two of the test compounds ( 2c and 3b ) showed potent anti‐inflammatory activity comparable to that of diclofenac with lower ulcerogenic effect relative to indomethacin. SAR study of the two series as cyclooxygenase inhibitors and anti‐inflammatory agents was also provided.     

Antineoplastic effect of β‐elemene on prostate cancer cells and other types of solid tumour cells

Objectives β‐Elemene, a natural compound extracted from over 50 different Chinese medicinal herbs and plants, has been effective in the treatment of hyperplastic and proliferative disorders such as prostatic hypertrophy, hysteromyoma and neoplasms. Our previous studies have demonstrated that β‐elemene exhibits strong inhibitory activity in ovarian cancer cells. The aim of the present study was to assess the effect of β‐elemene on prostate cancer cells as well as other types of tumour cells and to determine whether the effect of β‐elemene on prostate cancer cell death was mediated through the induction of apoptosis. Methods The MTT assay was used to evaluate the ability of β‐elemene to inhibit cellular proliferation in cancer cells. Cellular apoptosis was assessed by annexin V binding, TUNEL and ELISA‐based assays. Caspase activity was measured using a caspases assay kit. The protein levels of Bcl‐2, caspases, cytochrome c and poly(ADP‐ribose) polymerase (PARP) were analysed by Western blotting. Key findings Here, we showed that β‐elemene had an antiproliferative effect on androgen‐insensitive prostate carcinoma DU145 and PC‐3 cells. Treatment with β‐elemene also inhibited the growth of brain, breast, cervical, colon and lung carcinoma cells. The effect of β‐elemene on cancer cells was dose dependent, with IC50 values ranging from 47 to 95 µg/ml (230–465 µm ). TUNEL assay and flow cytometric analysis using annxin V/propidium iodide staining revealed that the percentage of apoptotic prostate cancer cells was increased by β‐elemene in a dose‐ and time‐dependent manner. Moreover, β‐elemene exposure resulted in a decreased Bcl‐2 protein level, increased cytochrome c release, and activated PARP and caspase‐3, ‐7, ‐9, and ‐10 in prostate cancer cells. Conclusions Overall, these findings suggest that β‐elemene exerts broad‐spectrum antitumour activity against many types of solid carcinoma and supports a proposal of β‐elemene as a new potentially therapeutic drug for castration‐resistant prostate cancer and other solid tumours.     

Synthesis and Evaluation of Novel 4‐Substituted Styryl Quinazolines as Potential Antimicrobial Agents

In an attempt to afford possible antibacterial and anti‐human immunodeficiency virus (HIV) agents, a series of 22 novel styryl quinazoline‐based heterocyclic entities were designed and synthesized. Various substituted aryl urea and thiourea cores were incorporated at position 4 of quinazoline, followed by styrylation of position 2, aiming at an augmented biological potential. The synthesized compounds were well characterized through IR, ¹H NMR, ¹³C NMR and elemental analyses. All compounds were screened for their in vitro anti‐HIV activity against the HIV‐1 (IIIB) and HIV‐2 (ROD) strains. The antibacterial activity was also evaluated against various pathogenic Gram‐positive and Gram‐negative bacterial strains.