Compound 3b Research Articles

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 μM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 μM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

Design, synthesis, and molecular dynamics simulation studies of some novel kojic acid fused 2-amino-3-cyano-4H-pyran derivatives as tyrosinase inhibitors.

A novel series of kojic acid fused 2-amino-3-cyano-4H-pyran derivatives were synthesized via a multicomponent reaction involving kojic acid, benzyloxy benzaldehyde, and malonitrile as tyrosinase inhibitors. Subsequently, the structures of the compounds were characterized using FT-IR, 1H-, and 13C-NMR spectroscopic analyses. The designed compounds fall into three series: (1) 4-benzyloxy-phenyl kojopyran 6a-e, (2) 3-benzyloxy- phenyl kojopyran derivatives 6f-j, and (3) 4-benzyloxy-3-methoxy-phenyl kojopyran derivative 6k-o. The assessment of tyrosinase inhibition activity was conducted using L-Dopa as the substrate. Among synthesized compounds, 2-amino-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b) demonstrated the highest antityrosinase activity with a competitive inhibition pattern (IC50 = 7.69 ± 1.99μM) as compared to the control agent kojic acid (IC50 = 23.64 ± 2.56µM). Since compound 6b was synthesized as a racemic mixture, in silico studies were performed for both R and S enantiomers. The R- enantiomer showed critical interactions compared with the S-enantiomer. Specifically, it established hydrogen bonds and hydrophobic interactions with crucial and highly conserved amino acids within the enzyme's binding site in the target protein. Moreover, the molecular dynamics simulations revealed that compound 6b demonstrated significant interactions with essential residues of the binding site, resulting in a stable complex throughout the entire simulation run. The drug-like and ADMET properties predictions showed an acceptable profile for compound 6b. Thus, it can serve as a drug candidate to develop more potent antityrosinase agents due to its low toxicity and its high inhibition activity.

Supramolecular networks featuring diverse array of noncovalent interactions in crystals of hydrazinylidene-benzothiazinediones: X-ray crystallographic, DFT and biochemical analysis

The intricate role of noncovalent interactions in numerous fields including chemistry, biology, catalysis, material science, and medicinal chemistry provides a continuous impetus towards the discovery of new synthons that stabilize the supramolecular architectures. In this regard, the current work presents a series of five hydrazinylidene-benzothiazinedione derivatives encompassing a wide plethora of noncovalent interactions. Despite the configurational similarity of their hydrazinylidene-benzothiazinedione component, the five crystallographic packing arrangements of 7a–c and 9a,b are unique. The principal intermolecular interactions are CH⋯O hydrogen bonds and weak CH···π interactions (Malone Type III). Inversion dimers based on CH⋯Cl interactions form for 7b while CH⋯N and CH⋯S interactions in 9a were also observed. Furthermore, the energetic properties of the supramolecular dimers, centrosymmetric (antiparallel oriented) arrangements in 7a and 7b while parallel oriented arrangements in 9a and 9b have been examined using a combined QTAIM/NCI plot methods. The medicinal chemistry potential against urease enzyme revealed compound 9b as the lead inhibitor with strong efficacy (IC50 = 0.92 ± 0.03 µM). In vitro results were complemented with molecular docking revelations where several key interactions were observed between the potent ligand and active site amino acids. ADMET profile also described compounds 7b and 9b as the best molecules with promising druglike profile.

Synthesis and biological evaluation of 3‐hydroxypyrazoles as aquaporin 9 inhibitors

AbstractA series of 3‐hydroxypyrazole derivatives have been synthesized by a base‐promoted reaction of nitro‐substituted donor–acceptor cyclopropanes with hydrazines. The synthesized compounds have been investigated for their ability to inhibit aquaporin 9 (AQP9) in rat Leydig cells (LC‐540). The protein data bank structure for AQP9 was predicted using homology modeling; and the protein–ligand interaction for the synthesized hydroxyl pyrazole derivatives were analyzed using molecular modeling and docking studies. The results of in silico analyses showed that compound 5b had a higher binding affinity with AQP9 than other compounds. Further, in vitro studies conducted in LC‐540 cells confirmed that compound 5b effectively inhibits AQP9. Hence, compound 5b may be used as an inhibitor in enhancing our understanding of AQP9 function, and in the treatment of several diseases.

Design, synthesis, and evaluation of dual-target inhibitors for the treatment of Alzheimer's disease.

Aβ1-42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aβ1-42 and protect nerve cells, and it can also penetrate the blood-brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl3-induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.

Pyrimidine Schiff Bases: Synthesis, Structural Characterization and Recent Studies on Biological Activities.

Recently, 5-[(4-ethoxyphenyl)imino]methyl-N-(4-fluorophenyl)-6-methyl-2-phenylpyrimidin-4-amine has been synthesized, characterized, and evaluated for its antibacterial activity against Enterococcus faecalis in combination with antineoplastic activity against gastric adenocarcinoma. In this study, new 5-iminomethylpyrimidine compounds were synthesized which differ in the substituent(s) of the aromatic ring attached to the imine group. The structures of newly obtained pyrimidine Schiff bases were established by spectroscopy techniques (ESI-MS, FTIR and 1H NMR). To extend the current knowledge about the features responsible for the biological activity of the new 5-iminomethylpyrimidine derivatives, low-temperature single-crystal X-ray analyses were carried out. For all studied crystals, intramolecular N-H∙∙∙N hydrogen bonds and intermolecular C-H∙∙∙F interactions were observed and seemed to play an essential role in the formation of the structures. Simultaneously, their biological properties based on their cytotoxic features were compared with the activities of the Schiff base (III) published previously. Moreover, computational investigations, such as ADME prediction analysis and molecular docking, were also performed on the most active new Schiff base (compound 4b). These results were compared with the highest active compound III.

Discovery of a novel androgen receptor antagonist, MEL-6, with stereoselective activity and optimization of its metabolic stability

A new chemical scaffold with antagonistic activity towards the androgen receptor (AR) was identified. The parent compound, (3-Methoxy-N-[1-methyl-2-(4-phenyl-1-piperazinyl)−2-(2-thienyl)ethyl]benzamide) referred to as MEL-6, binds in the ligand binding pocket of AR and induces an antagonistic conformation of the ligand binding domain, even in presence of the antagonist-to-agonist switch mutations W741C, T877A and F876L-T877A. MEL-6 has antiproliferative effects on several AR positive prostate cancer cell lines. We further identified AR as the specific target of MEL-6 since it demonstrates little effect on other steroid receptors. In LNCaP cells it also inhibits the androgen-regulated transcriptome. These findings identify MEL-6 as a promising candidate for treatment of patients with prostate tumors that have become resistant to current clinically used AR antagonists. Analytical studies on the chemical composition of MEL-6 identified the presence of four isomers (two enantiomeric pairs), among which one isomer is responsible for the antiandrogenic activity. We therefore developed a synthetic route towards the selective preparation of the active enantiomeric pair. Various MEL-6-like analogues had improved metabolic stability while maintaining antiandrogenic activity. Metabolite identification of MEL-6 derivatives pinpointed N-dealkylation of the piperazine as the main mode for inactivation by liver enzymes. For further structural optimization, MEL-6 derivatives were purchased or synthesized having alterations on the N-phenyl group of the piperazine, the benzoyl group and additionally substituting the thiophen-2-yl ring of MEL-6 to a phenyl ring. This optimization process resulted in compound 12b with sustained AR inhibition and a 4-fold increased half-life due to the 1-(5-chloro-2-methylphenyl)-piperazine substitution, thienyl-to-phenyl substitution and chloro in para-position of the benzoyl group.

New pyranopyrazole based derivatives: Design, synthesis, and biological evaluation as potential topoisomerase II inhibitors, apoptotic inducers, and antiproliferative agents

A new series of pyranopyrazole-based derivatives were designed and synthesized. The synthesized compounds were assessed for their cytotoxic efficacy against A549 human lung carcinoma and MCF-7 human breast carcinoma cell lines. Three compounds (1b, 4b, and 7b) exhibited 1.3- to 2.3-fold more antiproliferative activity than that of doxorubicin against the A549 cell line. In comparison to doxorubicin, compounds 1d and 3b were 4.1- and 1.04-fold, respectively more powerful against MCF-7 cancer cells. All the synthesized compounds were found to be more selective toward A549 cancer cells than the normal human fibroblast BJ cells. Of interest, compounds 1b and 7b exhibited promising cytotoxicity and SIs of 27.72 and 25.30, respectively, towards A549 cancer cells, higher than that of doxorubicin (SI 4.81). The most potent compounds 1b, 1d, 3b, 4b, and 7b were then subjected to in vitro Topo II inhibition assay. They showed IC50 values in the range of 2.07 to 8.86 µM. Of particular interest, compound 7b (IC50 = 2.07 µM), exhibited higher Topo II inhibitory activity than that of doxorubicin (IC50 = 2.56 µM). The significant Topo II inhibition of compound 7b was explained by molecular docking simulations into the Topo II active site. Compound 7b halted the cell cycle in the S phase in A549 cancer cells. It induced total apoptosis and necrosis of 20.73- and 4-fold, respectively, greater than the control. This evidence was supported by a 3.59-fold increase in the level of apoptotic caspase-9 and a remarkable elevation of the Bax/BCL-2 ratio. The physiochemical parameters of compound 7b were aligned with Lipinski’s rule of five.

MOLECULAR FIELD ANALYSIS AND DYNAMIC SIMULATION STUDIES OF 1,5-DISUBSTITUTED PYRAZOLINE-BASED MAO-A INHIBITORS FOR THE MANAGEMENT OF DEPRESSION

Depression, along with grief and anxiety, is currently one of the most common mental illnesses. It was placed 25th among the major diseases. QSAR (CoMFA) of 37 compounds with MAO-A inhibitory activity yielded the most significant QSAR model, m.3, with r2 = 0.963, SDEC= 0.129, q2 = 0.742, SDEP= 0.34. Using the lead likeness matrix, thirty-seven 1,5-disubstituted MAO-A inhibitors were developed and tested based on the QSAR models. The top 13 compounds were identified. Furthermore, compound 2B (ΔG: -10.3 kcal mol-1, RMSD: 0.151 Å) was selected among the top 13 hits obtained from molecular docking experiments. Significant interactions were also observed, including π-π contacts with Phe208, Tyr444, Trp407, and hydrogen bond interactions with Ala68 and Tyr69. Furthermore, dynamic modelling demonstrated that compound 2B (0.11 nm) has higher overall stability than clorgyline, with a lower RMSD value, and may reach equilibrium in the final 20-25 ns. In terms of RMSF, 2B produced around 0.34 nm with less variation than clorgyline. Throughout the simulation, 2B (No. of H-bond: 6) had more hydrogen bonding than clorgyline (No. of H-bond: 3) with the highest occupancy, i.e. 117.39% for GLU216, 29% for TYR444, and 49% for PRO72, and so on. Compound 2B was proven to be the most essential throughout the experiments. These new chemicals will be optimized in vitro and in vivo in the future. This study will surely contribute to the development of novel MAO-A inhibitors for the treatment of depression.

Design and synthesis of novel 3-amino-5-phenylpyrazole derivatives as tubulin polymerization inhibitors targeting the colchicine-binding site

As the basic unit of microtubules, tubulin is one of the most important targets in the study of anticarcinogens. A novel series of 3-amino-5-phenylpyrazole derivatives were designed and synthesized, and evaluates for their biological activities. Among them, a majority of compounds exerted excellent inhibitory activities against five cancer cell lines in vitro. Especially, compound 5b showed a strong antiproliferative activity against MCF-7 cells, with IC50 value of 38.37 nM. Further research indicated that compound 5b can inhibit the polymerization of tubulin targeting the tubulin colchicine-binding sites. Furthermore, 5b could arrest MCF-7 cells at the G2/M phase and induce MCF-7 cells apoptotic in a dose-dependent and time-dependent manners, and regulate the level of related proteins expression. Besides, compound 5b could inhibit the cancer cell migration and angiogenesis. In addition, 5b could inhibit tumor growth in MCF-7 xenograft model without obvious toxicity. All these results indicating that 5b could be a promising antitumor agent targeting tubulin colchicine-binding site and it was worth further study.

A piperazine- modified Schiff base sensor for highly selective detection of Zr (IV) ions: unveiling its antioxidant potential and regulatory effects on Zea mays growth

Piperazine functionalized Schiff bases 4(a-c) were synthesized by a condensation reaction which were thoroughly characterized by using various spectroscopic techniques like 1H NMR, 13C NMR, IR and mass spectrometry. X-ray crystallography was used to analyse synthesized compound 4b. The sensing capability of 4b was investigated towards the tetravalent form of the zirconium ion among other metal ions. The limit of detection and the association constant, were calculated to be 56.4 × 10−8 M and 5.36 × 105 M−1 respectively. The inclusion of additional metal ions had no effect on the selectivity of sensor 4b. The binding mechanism was clarified using 1HNMR spectroscopy, which was further verified computationally, using DFT. Also, the seed germination experiments were performed and effect of compound 4b was analyzed on the seedlings of Zea Mays. An investigation into molecular docking study using (5HQX) protein revealed that it had inhibitory effects on cytokinin oxidase. The protein and ligand effectively associate, as indicated by the lower binding energy of −9.69 kcal/mol. Therefore, compound 4b can act as a good, powerful inhibitor against cytokinin oxidase.

Synthesis and Biological Evaluation of 2-Azolylmethylene-3-(2H)-benzofuranone Derivatives as Potent Monoamine Oxidases Inhibitors.

A series of 2-azolylmethylene-3-(2H)-benzofuranone derivatives, 2-indolylmethylene-3-(2H)-benzofuranone and 2-pyrrolylmethylene-3-(2H)-benzofuranone derivatives, were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 1b, 3b, 6b, 7b, and 10b showed strong inhibitory activity against MAO-A, and compound 3b showed the highest potency and selectivity, with an IC50 value of 21 nM and a MAO-A selectivity index of 48. Compounds 3c, 4c, 9a, 9c, 10c, 11a, and 11c showed strong inhibitory activity against MAO-B, and compound 4c showed the highest potency and selectivity, with an IC50 value of 16 nM and a MAO-B selectivity index of >1100. Further analysis of these compounds indicated that compound 3b for MAO-A and compound 4c for MAO-B were competitive inhibitors, with Ki values of 10 and 6.1 nM, respectively. Furthermore, computational analyses, such as quantitative structure-activity relationship (QSAR) analysis of the 2-azolylmethylene-3-(2H)-benzofuranone derivatives conducting their pIC50 values with the Molecular Operating Environment (MOE) and Mordred, and molecular docking analysis using MOE-Dock supported that the 2-azolylmethylene-3-(2H)-benzofuranone derivatives are a privileged scaffold for the design and development of novel MAO inhibitors.

Design and cytotoxic activity of thiazolidinones via one-pot, three component reaction under microwave and traditional method

Treatment of sulfamethoxazole (SMZ ) (1) with different aromatic aldehydes 2a-f within few minutes (5-8 min) afforded the corresponding Schiff bases 3a-f which were subjected to react with thioglycolic acid (4) under refluxing toluene/dimethlformamide (DMF) in (1:1) ratio for 12-17 h, yielded N-(5-methylisoxazol-3-yl)-4-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)benzenesulfon- amide derivatives 5a-f. On the other hand, the same products 5a-f were obtained when SMZ (1) was treated with a mixture of the same aromatic aldehydes 2a-f and thioglycolic acid 4 via one-pot, three-component reaction under microwave irradiation. The key advantages of this process were high yields 79-88%, shorter reaction times 6-11 min., easy work-up, and problems associated with toxic solvent use (cost, safety, pollution) were avoided. The structures of newly compounds were elucidated by elemental and spectral analyses. Three compounds 5a, 5b and 5f were tested for cytotoxicity against four human cancer cell lines MCF-7, HePG2, HCT 116 and 116 PC-3. Compound 5b exhibited the most potent cytotoxic properties on HePG2 and PC-3. Furthermore, it showed inhabitory effect against MCF-7 and HCT 116 cells.
 KEY WORDS: Sulfamethoxazole, 4-Thiazolidinones, Schiff bases, Multicomponent reaction, Microwave, Traditional methods and cytotoxicity
 Bull. Chem. Soc. Ethiop. 2024, 38(2), 481-491. 
 DOI: https://dx.doi.org/10.4314/bcse.v38i2.15

Discovery of 1H-pyrazolo[3,4-b]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRASG12C-mutant non-small cell lung cancer

The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1H-pyrazolo[3,4-b]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC50 value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRASG12C-mutant non-small cell lung cancer NCI-H358 cells, with an IC50 value of 0.58 μM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRASG12C inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRASG12C mutant non-small cell lung cancer. Communicated by Ramaswamy H. Sarma

Synthesis, Characterization and In Vitro Anti-cancer Properties of Cationic Gemini Surfactants with Alkyl Chains in Human Breast Cancer

Gemini surfactants have unique advantages in various industries such as detergents, cosmetics, paints, and pharmaceuticals due to their versatile hydrophilic-lipophilic balance. Three novel cationic surfactants, derived from alkyl alcohol and epichlorohydrin, featuring multi-alkyl multiple quaternary-ammonium salts, were synthesized with the order of C4 > C6 > C8 alkyl groups. The structure of the synthetic compounds was determined using FTIR and 1H-NMR analysis. The anti-cancer properties of the Gemini surfactants were determined with the MCF-7 breast cancer cell line, using the MTT cytotoxicity assay. We found an increase in alkyl groups (C4 > C6 > C8), indicating that larger alkyl groups contribute to improved surface qualities. The compounds showed improved surface qualities and reduced critical micelle concentration (CMC). In addition, The results showed the significant anti-cancer potential of compound B1 on the breast cancer cell line. In comparison to compounds B2 and B3, the highest inhibition was observed at concentrations from 25 to 400 µg/mL, demonstrating 26.8% to 4.3% and 32% to 4.7%, inhibition, respectively.

Synthesis and biological evaluation of new nicotinic acid derivatives as potential anti-inflammatory agents with enhanced gastric safety profile

Two innovative series derived from nicotinic acid scaffold were synthesized and evaluated for their anti-inflammatory activity. Ibuprofen, celecoxib and indomethacin were used as standard drugs. All the newly synthesized compounds were in vitro screened for their anti-inflammatory activity adopting 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide dye (MTT), as well as Griess assays. The results showed that all compounds exhibited significant anti-inflammatory activity without affecting the viability of the macrophages compared to ibuprofen. In addition, compounds 4d, 4f, 4g, 4h and 5b exhibited the most potent nitrite inhibition activity and consequently superior anti-inflammatory activity with MTT results ranging between values 86.109 ± 0.51 to 119.084 ± 0.09. The most active compounds were subjected to evaluation of TNF-α, IL-6, iNOS and COX-2 levels in LPS/INF γ-stimulated RAW 264.7 macrophage cells in comparison to ibuprofen as a reference compound. The five compounds showed comparable inhibition potency of these inflammatory cytokines compared to ibuprofen. Same compounds were further in vivo evaluated for their anti-inflammatory activity via carrageenan induced arthritis in rats. Regarding the ulcerogenic profile, compound 4h showed mild infiltration of gastric mucosa superb to compound 5b displayed severe gastritis. Molecular docking of 4h and 5b in the COX-2 active site was performed to evaluate their preferential COX-2 inhibitory potency. The docking results were in accordance with the biological findings.

A galantamine–curcumin hybrid lacks the depressant side effect of acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors (AChEIs) are drugs that enhance cholinergic neuro-transmission and are used for the treatment of Alzheimer’s disease and myasthenia gravis. Common AChEIs include rivastigmine, donepezil and galantamine (GAL), but they can cause side effects like nausea, vomiting, depression and bradycardia. A potential link exists between AChEIs and increased depression risk. Recently, we have discovered a hybrid compound (4b) combining GAL and curcumin (CCN), which shows improved anticholinesterase activity and neuroprotective effects. It could be developed as a potential multitarget agent for neurodegenerative disorders. Here, we examine the compound’s depressant side effect on mice, comparing it to GAL and CCN. Tests were conducted twice using the tail suspension test (TST) and the forced swim test over an 8-day treatment period. The results showed that 4b lacked the depressant effect of GAL and even displayed a mild antidepressant effect similar to CCN in TST. This suggests that incorporating antidepressant fragments, like CCN, into AChEIs can potentially neutralize their depressive side effects.

Rational design, synthesis, analysis and antifungal activity of novel myristic acid derivatives as N-myristoyltransferase inhibitors

A demand for the discovery of new antifungal agents has rose significantly because of a rise in morbidity and related mortality due to systemic fungal infections. N-myristoyltransferase (NMT) has been recognized as a new target for the treatment of fungi infections in recent years. Herein, we report a new series of myristic acid derivatives as antifungal agents by inhibiting N-myristoyltransferase (NMT). The myristic acid derivatives were rationally designed by targeting NMT via docking studies and ADMET studies. The designed myristic acid derivatives were prepared by converting myristic acid to acid chloride followed by coupling with aryl amines to yield the title compounds. The synthesized compounds were purified and analyzed by IR, NMR and Mass spectral analysis. Thereafter, we perform the target NMT inhibition assay. In NMT inhibition assay results, the compound 3g (IC50 = 0.931 μM) had superior activity than other myristic acid derivatives and myristic acid (IC50 = 4.213 μM). In vitro antifungal screening activity results, the compound 3g was more active against Candida albicans (MIC50 =10.94 μg mL−1) than fluconazole (MIC50 = 17.76 μg mL−1). In case of Aspergillus niger (A. nig) strain, compound 3b (MIC50 =13.17 μg mL−1) shows better activity than fluconazole (MIC50 =16.30 μg mL−1). The illustration about the design, synthesis, analysis, and evaluation of myristic acid derivatives is reported.

Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 μM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 μM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.

Synthesis of 5-heptadecyl-4H-1,2,4-triazole incorporated indole moiety: Antiviral (SARS-CoV-2), antimicrobial, and molecular docking studies

Two series of Schiff bases and Mannich bases derived from 5-heptadecyl-4H-1,2,4-triazole hybrids of indole moiety have been synthesized. First, the acid-catalyzed reaction of N-substituted-1H-indole-3-carboxaldehydes with the modified fatty acid, 4-amino-5-heptadecyl-4H-1,2,4-triazole-3-thiol, afforded 1,2,4-triazole Schiff bases 5a-d. Treatment of 5a-d with some halo-compounds gave S-alkyl-1,2,4-triazoles 6a-d to 9a-d. Additionally, the reaction of 5a-d with different secondary amine and paraformaldehyde afforded Mannich base products 10a-d to 13a-d. Basically, viral infections are often followed by bacterial infections that require antimicrobial treatment. The antiviral bioassay revealed that compounds 6d and 7d exhibited significant antiviral activity against NRC-03-nhCoV with IC50 equal 8.7 and 8.925 μM, respectively. Next, the synthesized compounds were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria as well as yeast and fungi. Compound 5b exhibited effective antimicrobial activities against all microbial test strains. 5b revealed MIC values of 19.53 μg/mL against S. aureus, 39.063 μg/mL against E. coli, and 39.125 μg/mL against C. albicans. On top of that, the release of reducing sugars and proteins from the treated bacterial strains over the untreated bacterial strains was undertaken to describe the effect of compound 5b on the intact cells. Furthermore, scanning electron microscopy (SEM) has been applied to study the possible sterilization process of the antimicrobial compound 5b. The results indicated the possibility of destroying the cell membrane structure of microbes, resulting in incomplete microbial structures, and thus achieving inhibition. To putatively highlight the antiviral and antimicrobial activities of the potent compounds, they were subjected to molecular docking against the key viral and microbial protein targets.