Total Synthesis of 11‐Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage‐Gated Sodium Channels

11‐Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C?C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu₄N][Ph₃SnF₂], which directly constructs the crucial C?C bond at the C11 position in SEA. The Na_VCh‐inhibitory activities of SEA and its derivatives were evaluated by means of cell‐based assay. SEA showed an IC₅₀ value of (47±12) nm , which is approximately twice as potent as decarbamoyl‐STX (dcSTX).     

Synthesis of novel triazoloquinoxaline-pyrazole hybrids as antiproliferatives,EGFR inhibitors,and apoptosis inducers

Novel triazoloquinoxaline-pyrazole hybrids have been developed and synthesized. All derivatives' anticancer activity has been evaluated using Sulforhodamine-B (SRB) assay for cancer cell lines MCF-7, HepG-2, and HCT-116. Compound 12b was 2-fold more cytotoxic than Doxorubicin, while 12a , c demonstrated comparable cytotoxicity to the reference Doxorubicin. Further investigations on the most active derivatives 12a-c were done to study their inhibitory activity on two EGFR subtypes wild EGFR and mutant EGFR (L858R) tyrosine kinases in MCF-7 cell lines. Compound 12b exhibited potent inhibitory activity toward wild EGFR (IC₅₀: 0.98 μM) when compared to Gefitinib (IC₅₀:18.07 μM). 12b also possessed a marked inhibition against mutant EGFR (L858R-TK) exhibiting (IC₅₀:27.45 μM) in comparison to Lapatinib (IC₅₀: 61.06 μM). Compound 12b improved the active Caspase-3 value and the BAX/Bcl-2 reference. Furthermore, 12b showed G2/M cell cycle arrest induced apoptosis in cell line MCF-7. In addition, the most active derivatives have been orally bioavailable as shown in the in silico determination of the ADME characters. The binding pattern of compound 12b was also studied by molecular docking.     

Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors

We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using ¹H-NMR, ¹³C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE₆ cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC₅₀ value of 160 nM. Compound 13b exhibited an enzyme IC₅₀ value of 4.9 µM. However, it exhibited a potent antiviral EC₅₀ value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC₅₀ value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.     

Nitrostyrene Derivatives of Adenosine 5′-Glutarates as Selective Inhibitors of the Epidermal Growth Factor Receptor Protein Tyrosine Kinase

The syntheses and biological activities of some nitrostyrene derivatives of adenosine 5′-glutarates, a novel class of selective, bi-substrate-type inhibitors of the EGF receptor protein tyrosine kinase with IC₅₀ values around 1 μM . Only marginal inhibition of the tyrosine kinases v-able and c-src and of the serine/threonine kinase PKC was observed. Compounds 8, 9, 11 , and 12 – lacking the adenosine moiety – were ten times less active than the most potent derivatives, whereas 17 – lacking the nitrostyryl part – showed no inhibitory activity at all. Most of the compounds showed potent antiproliferative activity against an EGF-dependent mouse keratinocyte cell line.     

Design,synthesis, and evaluation of novel combretastatin A-4 based chalcone derivatives as anticancer agents

A series of combretastatin A-4 based chalcones ( 14a-l ) were designed, synthesized and these compounds examined for inhibitory effects on the proliferation of human lung (A549), breast (MCF-7), melanoma (A375), and colon (HT-29) carcinoma cells. Compounds 14b , 14c , 14e , 14h , and 14i (tri/dimethoxy, methyl, and mono/dinitro derivatives) have exhibited the most potent antiproliferative activity with IC₅₀ < 2 μM and the hexa methoxy derivative 14b , the most promising one, which displayed the potent inhibitory activities in MCF-7 (IC₅₀: 10 nM), A375 (IC₅₀: 12 nM), and A549 (IC₅₀: 65 nM) cell lines, and is 18 times more potent than the CA-4. Compound 14b represents a new scaffold and the results provide insights into further development of anticancer agents.     

Design,synthesis, anticancer activity,and in silico studies of novel imidazo[1,2-a]pyridine based 1H-1,2,3-triazole derivatives

A novel series of imidazo[1,2-a]pyridine based 1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their anticancer activity against two different human cancer cell lines. Most of the synthesized compounds displayed anticancer activity with IC₅₀ values from 2.35 to 120.46 μM. Furthermore, compounds 9b , 9c, 9d, 9f , and 9j showed potent inhibitory activity against cancer cell lines, with IC₅₀ values close to that of standard drug. It is important to note that compound 9d was more potent than the standard drug cisplatin with IC₅₀ values of 10.89 and 2.35 μM against Hela cell line and MCF-7 cell line, respectively.     

Phloroglucinol Derivatives from Dryopteris crassirhizoma as Potent Xanthine Oxidase Inhibitors

Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC₅₀) value of 6.3 µM, similar to that of allopurinol (IC₅₀ = 5.7 µM) and better than that of oxypurinol (IC₅₀ = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3′ is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC₅₀ = 20.9 µM). Representative inhibitors (1–4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.     

Synthesis of 4‐Heteroaryl–Quinazoline Derivatives as Potential Anti‐breast Cancer Agents

4‐Heteroaryl or heteroalkyl–quinazoline derivatives were prepared as dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibitors. The new compounds were tested for their dual enzyme inhibition as well as their cytotoxic activity on MCF7 cell line. The results indicated that almost all the compounds showed moderate dual inhibition of both enzymes. Compound 3 (methyl piperidine‐4‐carboxylate derivative) showed the highest inhibitory activity against both enzymes with IC₅₀ 97.6 and 64.0 µM against EGFR and VEGFR‐2 kinases, respectively. Most of the test compounds showed potent to moderate antitumor activity on MCF7 cell line. Five compounds ( 3 , 9c , 11 , 13 , and 15b ) showed potent cytotoxic activity with IC₅₀ values between 10 and 17 µM .     

Design,Synthesis, and Thrombin Inhibitory Activity Evaluation of Some Novel Benzimidazole Derivatives

Some benzimidazole derivatives were designed and screened via molecular docking. Six compounds which obtained high scores were selected for synthesis and all compounds were characterized by ¹H‐ and ¹³C‐NMR, and HR‐ESI‐MS. Subsequently, these compounds were evaluated for their inhibitory activities on thrombin. Compound 5a (IC₅₀ 3.11 nm ) showed a better activity than the reference argatroban (IC₅₀ 9.88 nm ). These results, along with related molecular model studies, indicated that 5a could be a potential thrombin inhibitor for further research.     

Saxitoxin

The paralytic agent (+)‐saxitoxin (STX), most commonly associated with oceanic red tides and shellfish poisoning, is a potent inhibitor of electrical conduction in cells. Its nefarious effects result from inhibition of voltage‐gated sodium channels (Na_Vs), the obligatory proteins responsible for the initiation and propagation of action potentials. In the annals of ion channel research, the identification and characterization of Na_Vs trace to the availability of STX and an allied guanidinium derivative, tetrodotoxin. The mystique of STX is expressed in both its function and form, as this uniquely compact dication boasts more heteroatoms than carbon centers. This Review highlights both the chemistry and chemical biology of this fascinating natural product, and offers a perspective as to how molecular design and synthesis may be used to explore Na_V structure and function.     

Novel silicon-containing drugs derived from the indomethacin scaffold: Synthesis, characterization and evaluation of biological activity

Synthesis, spectroscopic characterization and in vitro pharmacological and cancer cell growth inhibitory activity studies of new silicon-containing compounds based on the indomethacin scaffold are now reported. Amidation of the indomethacin carboxylate group using amino-functional silanes generated a series of novel lipophilic derivatives of indomethacin. The pharmacological activity of these derivatives tested against human recombinant cyclooxygenase-1 and 2 demonstrated that the silicon-containing derivatives are cyclooxygenase-2 (COX-2) selective. The silicon-containing amides of indomethacin demonstrated in vitro growth inhibitory activity against human MiaPaCa-2 pancreatic carcinoma cells at low μM concentrations. The 3a and 3c derivatives exhibited the most potent in vitro antiproliferative activity, with IC₅₀ <6.0 μM, compared to unmodified indomethacin having an IC₅₀100 μM. We dedicate this paper to Prof. Mitsuo Kira, outstanding organosilicon chemist and valued friend.     

Design,synthesis, biological evaluation and molecular docking of novel substituted 1-ethyl-1<Emphasis Type="Italic">H</Emphasis>-benzimidazole fluorinated derivatives as thrombin inhibitors

Six novel substituted 1-ethyl-1H-benzimidazole fluorinated derivatives were designed and synthesised based on computer-aided simulation. The structures of the target compounds were characterised by ¹H NMR, ¹³C NMR, ¹⁹F NMR and FT-ICR-MS. The preliminary screening inhibition rate data of synthesised compounds were more than 80 %. Compounds 12a and 12f were evaluated for their anti-thrombin activity in vitro (IC₅₀). The tested data indicated that the compounds showed better thrombin inhibitory activity than reference drug argatroban (9.88 ± 2.26 nM). Especially, compound 12f was the most potent derivative with an IC₅₀ of 3.21 ± 0.57 nM and could act as a candidate compound for further exploration of thrombin inhibitor.     

Synthesis and Bioactivity of Substituted Benzoylguanidine Derivatives as Potent Na+/H+ Exchanger Inhibitors

A novel series of substituted benzoylguanidine derivatives were designed and synthesized in order to evaluate their NHE1 inhibitory activity. Most of them were found to inhibit NHE1‐mediated platelet swelling in a concentration‐dependent manner, and eight compounds showed more potent NHE1 inhibitory activity than Cariporide. Compound 6f with an IC₅₀ value of 1.08×10^?10 mol·L^?1, was 39 times more potent than lead compound CPU‐X‐050420 in vitro tests.     

Thiazolidinediones as a Novel Class of Algicides Against Red Tide Harmful Algal Species

This paper reports the synthesis of 28 thiazolidinedione derivatives along with their algicidal activity against microalgae causing harmful algal blooming. Among the 28 compounds tested, most showed effective algicidal activity against Heterosigma akashiwo, Chattonella marina, and Cochlodinium polykrikoides, while non-harmful algae were relatively tolerant to these thiazolidinedione derivatives. Compounds 6, 13, and 22 were the most potent against C. polykrikoides with IC₅₀ values <0.5 μM. Among the thiazolidinedione derivatives tested, compounds 7, 13, 27, and 28 were extremely competent and selective to C. polykrikoides with IC₅₀ values ranging from 0.1 to 2 μM, while C. marina and H. akashiwo showed an IC₅₀ value ranging from 30 to 130 μM. These results show that some thiazolidinedione derivatives can act as potent algicides against harmful algal blooms.     

Design,synthesis, in vitro and in silico studies of naproxen derivatives as dual lipoxygenase and α-glucosidase inhibitors

A series of 28 novel naproxen derivatives (4a-f, 5a-f, 6a-d, 7a-f, and 8a-f) have been designed, synthesized, and characterized. The synthesized derivatives were assessed as dual inhibitors for 15-lipoxygenase (LOX) and α-glucosidase enzymes and checked for cytotoxicity and ADME studies. The inhibitory potential of naproxen derivatives for 15- LOX was checked through two different methods, the UV absorbance method and the Chemiluminescence method. The biological activities result revealed that through the UV absorbance method, compound 4f (IC₅₀ 21.31 ± 0.32 µM) was found potent among the series followed by compounds 4e (IC₅₀ 36.53 ± 0.51 µM) and 4d (IC₅₀ 49.62 ± 0.12 µM) against standard drug baicalein (IC₅₀ 22.46 ± 1.32 µM) and quercetin (IC₅₀ 2.34 ± 0.35 µM), while through chemiluminescence method tested compounds showed significant 15-LOX inhibition at the range of IC₅₀ 1.13 ± 0.62 µM ?123.47 ± 0.37 µM. Among these compounds, 4e (IC₅₀ 1.13 ± 0.62 µM), 5b (IC₅₀ 1.19 ± 0.43 µM), 8c (IC₅₀ 1.23 ± 0.35 µM) were found most potent inhibitors against quercetin (IC₅₀ 4.86 ± 0.14 µM), and baicalein (IC₅₀ 2.24 ± 0.13 µM). The chemiluminescence method was found more sensitive than the UV method to identify 15-LOX inhibitors. Interestingly all synthesized compounds showed significant α-glucosidase inhibitory activity (IC₅₀ 1.0 ± 1.13 µM ? 367.2 ± 1.23 µM) even better than the standard drug acarbose (IC₅₀ 375.82 ± 1.76 µM), while compound 6c (IC₅₀ 1.0 ± 1.13 µM) and 7c (IC₅₀ 1.1 ± 1.17 µM) were found most potent compounds among the series even many folds better than the standard drug. The cell viability results showed that all compounds were less toxic, maintained cellular viability at the range of 99.8 ± 1.3% to 63.7 ± 1.5%. ADME and molecular docking studies supported drug-likeness and binding interactions of compounds with the targeted enzymes.     

Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na(V)1.4 and Na(V)1.5

Skeletal analogues of saxitoxin (STX) that possess a fused-type tricyclic ring system, designated FD-STX, were synthesized as candidate sodium ion channel modulators. Three kinds of FD-STX derivatives 4a-c with different substitution at C13 were synthesized, and their inhibitory activity on sodium ion channels was examined by means of cell-based assay. (-)-FD-STX (4a) and (-)-FD-dcSTX (4b), which showed moderate inhibitory activity, were further evaluated by the use of the patch-clamp method in cells that expressed Na(V)1.4 (a tetrodotoxin-sensitive sodium channel subtype) and Na(V)1.5 (a tetrodotoxin-resistant sodium channel subtype). These compounds showed moderate inhibitory activity towards Na(V)1.4, and weaker inhibitory activity towards Na(V)1.5. Uniquely, however, the inhibition of Na(V)1.5 by (-)-FD-dcSTX (4b) was "irreversible".     

Synthesis,Biological Evaluation,and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC₅₀ values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.     

Design,synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

A series of novel thiazolidine-4-one derivatives was synthesized by reacting 1,4-disubstituted hydrazine carbothioamides with diethyl azodicarboxylate. The structures were confirmed by spectroscopic data as well as single-crystal X-ray analyses. The antiproliferative activity of the synthesized compounds was investigated against four human cancer cell lines using an MTT assay. Compounds 5d, 5e, and 5f revealed the most potent antiproliferative activity with GI₅₀ values ranging from 0.70 µM to 1.20 µM, compared to doxorubicin GI₅₀ value = 1.10 µM. Compounds 5d, 5e, and 5f were further investigated for their inhibitory activities against CDK2 and EGFR as potential targets for their molecular mechanism. Compounds 5e and 5f have showed potent inhibitory activity to CDK2 enzyme with IC₅₀ values of 18 and 14 nM, which is more potent than the reference dinaciclib (IC₅₀ = 20 nM). Moreover, compounds 5e and 5f were the most potent EGFR inhibitors, with IC₅₀ values of 93 and 87 nM, respectively, compared to the reference erlotinib (IC₅₀ = 70 nM). In addition, the most potent derivatives were tested for their apoptotic activity against caspases 3, 8, and 9, and the results showed that compounds 5d, 5e, and 5f revealed a greater increase in active caspases 3,8 and 9 than doxorubicin. Also, compounds 5d, 5e, and 5f elevated cytochrome C levels in the MCF-7 human breast cancer cell line by about 15.5, 15.8, and 16.5 times, respectively. Finally, a molecular docking study was performed to investigate the binding sites of these compounds within the active sites of CDK2 and EGFR targets, and the results confirmed that the most potent CDK2 and EGFR inhibitor 5h also have showed the highest docking score.     

Benzoylquinazolinone derivatives as new potential antidiabetic agents: α-Glucosidase inhibition,kinetic, and docking studies

Benzoylquinazolinone derivatives 3a–n were synthesized via a simple one-step reaction, and evaluated for in vitro α-glucosidase inhibitory activity. Compounds 3d , 3f–g , 3i , and 3m–n showed more inhibitory activity than standard drug acarbose (IC₅₀ = 750.0 ± 1.5 μM), and among them, compound 3d displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 261.6 ± 0.1 μM). The kinetic analysis of the compound 3d revealed that this compound inhibited α-glucosidase in a competitive manner (K_i = 255 μM). The docking studies were applied to predict binding modes of the synthesized compounds in active site of α-glucosidase.     

Virtual screening of protein kinase C inhibitors from natural product library to modulate general anaesthetic effects

Protein kinase C (PKC) plays a key role in neurotransmission in the central nervous system, and targeting PKC domain is considered as a strategy to modulate the anaesthetic effects. In this study, we described a synthetic pipeline to perform high-throughput virtual screening against a large library of 3D structural natural products released recently in order to discover those potential PKC modulators. A total of 100 natural products with top scores were raised, from which 12 promising candidates were tested to determine their inhibitory potencies against PKC. As might be expected, the promiscuous kinase inhibitor staurosporine showed a high PKC inhibitory activity (IC₅₀ = 64 nM), and other two tested compounds, i.e. fisetin and tetrahydropapaverine, were also highly potent with their activities at nanomolar level (IC₅₀ = 370 and 190, respectively).