Compounds 4l Research Articles

Synthesis and cytotoxicity evaluation of novel 1,8-acridinedione derivatives bearing phthalimide moiety as potential antitumor agents

In this study, we aimed to develop hybrid antitumor compounds by synthesizing and characterizing novel N-substituted acrididine-1,8-dione derivatives, designed as hybrids of phthalimide and acridine-1,8-diones. We employed a three-step synthetic strategy and characterized all compounds using IR, 1H NMR, 13C NMR, and LC–MS. The cytotoxicity and antitumor activity of five compounds (8c, 8f, 8h, 8i, and 8L) against four cancer cell lines (H460, A431, A549, and MDA-MB-231) compared to human skin fibroblast cells were evaluated. Among the synthesized compounds, compound 8f showed promising activity against skin and lung cancers, with favorable IC50 values and selectivity index. The relative changes in mRNA expression levels of four key genes (p53, TOP2B, p38, and EGFR) in A431 cells treated with the five synthesized compounds (8c, 8f, 8h, 8i, and 8L) were also investigated. Additionally, molecular docking studies revealed that compound 8f exhibited high binding affinity with TOP2B, p38, p53, and EGFR, suggesting its potential as a targeted anticancer therapy. The results obtained indicate that N-substituted acrididine-1,8-dione derivatives have the potential to be developed as novel antitumor agents with a dual mechanism of action, and compound 8f is a promising candidate for further investigation.

Discovery of novel 4,5-diphenyl-imidazol-α-aminophosphonate hybrids as promising anti-diabetic agents: Design, synthesis, in vitro, and in silico enzymatic studies

Herein, a novel series of 4,5-diphenyl-imidazol-α-aminophosphonate hybrids 4a-m was designed, synthesized, and evaluated as new anti-diabetic agents. These compounds were evaluated against two important target enzymes in the diabetes treatment: α-glucosidase and α-amylase. These new compounds were synthesized in three steps and characterized by different spectroscopic techniques. The in vitro evaluations demonstrated that all the synthesized compounds 4a-m were more potent that standard inhibitor acarbose against studied enzymes. Among these compound, the most potent compound against both studied enzymes was 3-bromo derivative 4l. The latter compound with IC50 = 5.96 nM was 18-times more potent than acarbose (IC50 = 106.63 nM) against α-glucosidase. Moreover, compound 4l with IC50 = 1.62 nM was 27-times more potent than acarbose (IC50 = 44.16 nM) against α-amylase. Molecular docking analysis revealed that this compound well accommodated in the binding site of α-glucosidase and α-amylase enzymes with notably more favorable binding energy as compared to acarbose.

Synthesis, Antifungal, and Antibacterial Activities of Novel Benzoylurea Derivatives Containing a Pyrimidine Moiety.

To explore more efficient and less toxic antibacterial and antifungal pesticides, we utilized 2,6-difluorobenzamide as a starting material and ultimately synthesized 23 novel benzoylurea derivatives containing a pyrimidine moiety. Their structures were characterized and confirmed by 1H NMR, 13C NMR, 19F NMR, and HRMS. The bioassay results demonstrated that some of the title compounds exhibited moderate to good in vitro antifungal activities against Botrytis cinerea in cucumber, Botrytis cinerea in tobacco, Botrytis cinerea in blueberry, Phomopsis sp., and Rhizoctonia solani. Notably, compounds 4j and 4l displayed EC50 values of 6.72 and 5.21 μg/mL against Rhizoctonia solani, respectively, which were comparable to that of hymexazol (6.11 μg/mL). Meanwhile, at 200 and 100 concentrations, the target compounds 4a-4w exhibited lower in vitro antibacterial activities against Xanthomonas oryzae pv. oryzicola and Xanthomonas citri subsp. citri, respectively, compared to those of thiodiazole copper. Furthermore, the molecular docking simulation demonstrated that compound 4l formed hydrogen bonds with SER-17 and SER-39 of succinate dehydrogenase (SDH), providing a possible explanation for the mechanism of action between the target compounds and SDH. This study represents the first report on the antifungal and antibacterial activities of novel benzoylurea derivatives containing a pyrimidine moiety.

Chemo-/Regio-Selective Synthesis of Novel Functionalized Spiro[pyrrolidine-2,3'-oxindoles] under Microwave Irradiation and Their Anticancer Activity.

A novel series of nitrostyrene-based spirooxindoles were synthesized via the reaction of substituted isatins 1a-b, a number of α-amino acids 2a-e and (E)-2-aryl-1-nitroethenes 3a-e in a chemo/regio-selective manner using [3+2] cycloaddition (Huisgen) reaction under microwave irradiation conditions. The structure elucidation of all the synthesized spirooxindoles were done using 1H and 13C NMR and HRMS spectral analysis. The single crystal X-ray crystallographic study of compound 4l was used to assign the stereochemical arrangements of the groups around the pyrrolidine ring in spiro[pyrrolidine-2,3'-oxindoles] skeleton. The in vitro anticancer activity of spiro[pyrrolidine-2,3'-oxindoles] analogs 4a-w against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines shows promising results. Out of the 23 synthesized spiro[pyrrolidine-2,3'-oxindoles], while five compounds (4c, 4f, 4m, 4q, 4t) (IC50 = 34.99-47.92 µM; SI = 0.96-2.43) displayed significant in vitro anticancer activity against human lung (A549) cancer cell lines, six compounds (4c, 4f, 4k, 4m, 4q, 4t) (IC50 = 41.56-86.53 µM; SI = 0.49-0.99) displayed promising in vitro anticancer activity against human liver (HepG2) cancer cell lines. In the case of lung (A549) cancer cell lines, these compounds were recognized to be more efficient and selective than standard reference artemisinin (IC50 = 100 µM) and chloroquine (IC50 = 100 µM; SI: 0.03). However, none of them were found to be active as compared to artesunic acid [IC50 = 9.85 µM; SI = 0.76 against lung (A549) cancer cell line and IC50 = 4.09 µM; SI = 2.01 against liver (HepG2) cancer cell line].

Novel 2-Amino-pyrano[3,2-c]quinoline-3-carbonitrile Derivatives Bearing Benzyloxy Phenyl Moiety as Butyrylcholinesterase Inhibitors: Design, Synthesis, In Vitro Evaluation, and Molecular Docking Studies

Background: Alzheimer’s disease (AD), the main form of dementia, is a multifactorial neurodegenerative disease, and several hypotheses have been proposed for its pathogenesis. Among them, cholinergic hypofunction is the main reason and plays a significant role in cognitive impairment. According to this theory, ChE inhibitors improve the performance of the cholinergic system and increase memory function. Thus, this study investigated a novel series of 2-amino-pyrano[3,2-c]quinoline-3-carbonitrile derivatives bearing benzyloxy phenyl moiety as ChE enzyme inhibitors. Methods: The synthesized compounds 6a-o are divided into three series based on benzyloxy phenyl moiety. The structure of all compounds was identified by the NMR (1 H and 13C) and IR spectra. Then, their inhibitory activities against ChE enzymes were evaluated by Ellman’s spectrophotometrical method. The kinetic and molecular docking studies were performed for compound 6l as the most potent butyrylcholinesterase (BChE) inhibitor. Results: The 2-amino-4-(4-((4-fluorobenzyl)oxy)-3-methoxyphenyl)-5-oxo-5,6-dihydro-4H-pyrano[3,2-c] quinoline-3-carbonitrile (6l) demonstrated the best anti-BChE activity with a half maximal inhibitory concentration value of 1.00±0.07. The kinetic and molecular docking studies confirmed that 6l is a mixed inhibitor and binds to both the anionic catalytic site and peripheral anionic site (PAS) of BChE. In silico study approved that the methoxy group on the middle phenyl ring has a significant role in interacting with the PAS of the enzyme. Conclusion: These findings indicated that 2-amino-pyrano[3,2-c]quinoline-3-carbonitrile derivatives bearing benzyloxy phenyl moiety have therapeutic potential as BChE inhibitors in the last stages of AD.

DOCKING STUDIES OF INDOLE ASSIMILATED PYRAZOLINE MOLECULAR HYBRIDS: DESIGN, SYNTHESIS AS ANTIINFLAMMATORY AGENTS AND ANTICANCER AGENTS

A series of novel compounds (4a-4l) have been synthesized by Claisen-Schmidt condensation, Schiff’s base and Cyclization mechanism. All the molecule structures were affirmation by IR, 1H NMR and Mass spectral data. The synthesized hybrids were screened for in vivo anti-inflammatory and invitro anticancer activities. Ant inflammatory activity was performed using carrageenan induced rat paw edema method using Diclofenac as standard drug. The anticancer activity has been assessing by using MTT assay against MCF7 and SKOV3 cell lines and Doxorubicin was used as reference standard. Among the compounds compound 4l exhibited the highest % inhibition of 98.4 when compared with the standard Diclofenac 94.2%.Compound 4f exhibited the lowest IC50 at concentration of 20.01µg against MCF7 cell lines and 32.87µg against SKOV3 cell lines. The molecular docking studies was performed using the Ligprep tool of Schrodinger suite. This study revealed that novel thiazolidne-4-one-pyrazole hybrids(4a-4j) had good interaction with the active site of EGFR receptor. Among the docked compounds, dock score of the compounds ranged from from -3.186 to -5.212. The highest score was exhibited by 4f with -5.212 with Glide binding energy of -34.697 Kcal/mol.

Synthesis of Novel Carboxamide Derivatives: Insecticidal Activity, Acetylcholinesterase Activity and In Silico Calculations

The insecticidal activity of carboxamide derivatives was investigated against both larvae and adults of Myzus percisace (Sulzer) (Hemiptera: Aphididae), Leptinotarsa decemlineata (Coleoptera: Chrysomelidae), and Trialeurodes vaporariorum (Hemiptera: Aleyrodidae) in different concentrations. The synthesized compounds were obtained good yield, and their molecular structures were confirmed by FTIR, NMR, and MALDI-TOF/MS. The compound 3o was found to be the most active against Leptinotarsa decemlineata adults, while the compound 3l was found against larvae. Furthermore, the compounds were evaluated against acetylcholinesterase (AChE) enzyme, and two of the compounds (3n and 3o) showed moderate inhibitory effect against both commercial acetylcholinesterase (0.18 ± 0.01 and 0.13 ± 0.01 μM) and M. percisace adult homogenate (0.65 ± 0.02 and 0.24 ± 0.01 μM), respectively. In silico molecular docking and ADME properties were performed.

Design, synthesis, and evaluation of new benzimidazole‏ ‏‎thiourea ‎derivatives as antitumor agents.

Novel benzimidazole thiourea derivatives were designed and synthesized based on sorafenib as a lead compound. The benzimidazole moiety was traded by the pyridine ring to enhance the hydrophobic interaction and retain hydrogen bonding in the hinge region, while lipophilic moieties with different bulkiness were employed in the deep hydrophobic pocket for better hydrophobic interactions. Thiourea as a urea bioisostere was also utilized. Substantial activity was demonstrated against a leukemia subpanel in an in vitro antitumor screening at the NCI. In the single-dose assay, compounds 7i, 7j, and 7l had a GI%) higher than sorafenib against most leukemia cell lines (GI% = 86.2%-137.1%), while in the five-dose assay, compound 7l outperformed sorafenib against the HL-60(TB) and SR leukemia cell lines in terms of GI50 , TGI, and LC50 . Compound 7l also caused cycle arrest at the G0-G1 and S phases in the HL-60(TB) leukemia cell line and induced apoptosis via elevating the Bax/Bcl-2 ratio and increasing caspases 3, 7, and 9 by 5.1-, 3.2-, and 5.2-fold, respectively. Compounds 7i, 7j, and 7l also inhibited the vascular ‎endothelial growth factor receptor-2 (VEGFR-2), B-Raf(V600E) , and platelet-derived growth factor receptor ‎beta (PDGFR-β) enzymes with an IC50 range of 0.063-0.44 μM. COMPARE analysis and a molecular docking study were also performed to predict the possible mechanism of action and binding mode, respectively.

The amide derivative of anticopalic acid induces non-apoptotic cell death in triple-negative breast cancer cells by inhibiting FAK activation

Anticopalic acid (ACP), a labdane type diterpenoid obtained from Kaempferia elegans rhizomes, together with 21 semi-synthetic derivatives, were evaluated for their cancer cytotoxic activity. Most derivatives displayed higher cytotoxic activity than the parent compound ACP in a panel of nine cancer cell lines. Among the tested compounds, the amide 4p showed the highest cytotoxic activity toward leukemia cell lines, HL-60 and MOLT-3, with IC50 values of 6.81 ± 1.99 and 3.72 ± 0.26 µM, respectively. More interestingly, the amide derivative 4l exhibited cytotoxic activity with an IC50 of 13.73 ± 0.04 µM against the MDA-MB-231 triple-negative breast cancer cell line, which is the most aggressive type of breast cancer. Mechanistic studies revealed that 4l induced cell death in MDA-MB-231 cells through non-apoptotic regulated cell death. In addition, western blot analysis showed that compound 4l decreased the phosphorylation of FAK protein in a concentration-dependent manner. Molecular docking simulations elucidated that compound 4l could potentially inhibit FAK activation by binding to a pocket of FAK kinase domain. The data suggested that compound 4l could be a potential FAK inhibitor for treating triple-negative breast cancer and worth being further investigated.

Novel coumarin-chalcone derivatives: Synthesis, characterization, antioxidant, cyclic voltammetry, molecular modelling and biological evaluation studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors

In this study, a total of 12 coumarin-chalcone derivatives, 6 of which are original were synthesized. The structures of the newly synthesized compounds were elucidated by 1H NMR, 13C NMR, IR, and elemental analysis methods (7g-7l). The antioxidant potencies measured by using CUPRAC method (Trolox equivalent total antioxidant capacity) were as follows: 7j > 7i > 7c > 7d > 7k > 7l > 7f > 7h > 7e > 7g > 7a >7b. Furthermore, the compounds were evaluated against human carbonic anhydrases I, II, acetylcholinesterase and α-glycosidase enzymes. Compounds 7c, 7e, 7g, 7i, 7j and 7l showed promising human carbonic anhydrase I inhibition compared to the standard Acetazolamide (Ki: 16.64 ± 4.72–49.82 ± 5.82 nM vs Ki: 57.64 ± 5.41 nM). In addition, all compounds exhibited strong inhibition against acetylcholinesterase and α-glycosidase. Ki values were between 2.39 ± 0.97–9.35 ± 3.95 nM (Tacrine Ki: 13.78 ± 4.36 nM) for acetylcholinesterase, and 14.49 ± 8.51–75.67 ± 26.38 nM (Acarbose Ki: 12600 ± 78.00 nM) for α-glycosidase. Binding of 7g was predicted using molecular docking and stability of the complex was confirmed with molecular dynamics simulations which shed a light on the observed activity against acetylcholinesterase. Finally, cyclic voltammetry was also used for the electrochemical characterization of the synthesized compounds.

Design, synthesis, and biological activity of new 8-decylthio-10-methylthio-pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

A series of new 8-decylthio-10-methylthio-pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives was prepared and characterized by FTIR, 1H NMR, 13C NMR, and HRMS. The bioassay results revealed that the title compounds had moderate to excellent insecticidal activities against Aphis fabae at a concentration of 500 mg/L. Among them, 8-(decylthio)-2-((4-chlorophenoxy)methyl)-5-propyl-10-(methylthio)-5,6-dihydropyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine (4l) exhibited the highest insecticidal activity, with 95% mortality. Moreover, 8-(decylthio)-2-((2,4-dichlorophenoxy)methyl)-5-propyl-10-(methylthio)-5,6-dihydropyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine (4i) showed broad-spectrum postemergence herbicidal activities against Abutilon theophrasti, Amaranthus spinosus, Chenopodium album, Digitaria sanguinalis, Echinochloa crusgalli, and Setaria viridis, which were equivalent to the positive control flumetsulam. However, all new synthesized compounds displayed weak fungicidal activity against four kinds of phytopathogenic fungi including Botrytis cinerea, phytophythora capsici, Elsinoe fewcetti, and Diaporthe medusaea. Compound 4l with remarkable insecticidal activity, and compound 4i with excellent herbicidal activity could be promising lead compounds for further investigation.

New Schiff bases derived from dimethylpyridine-1,2,4-triazole hybrid as cytotoxic agents targeting gastrointestinal cancers: Design, synthesis, biological evaluation and molecular docking studies

In this research, a series of novel hybrid structures of dimethylpyridine-1,2,4-triazole Schiff bases were designed, synthesized, and evaluated for their in vitro cytotoxic potency on several human gastrointestinal cancer cells (EPG, Caco-2, LoVo, LoVo/Dx, HT29) and normal colonic epithelial cells (CCD 841 CoN). Schiff base 4h was the most potent compound against gastric EPG cancer cells (CC50 = 12.10 ± 3.10 μM), being 9- and 21-fold more cytotoxic than 5-FU and cisplatin, respectively. Moreover, it was not toxic to normal cells. Regarding the cytotoxicity against colorectal cancer cells, compounds 4d and 4l exhibited good activity against HT29 cells (CC50 = 52.80 ± 2.80 μM and 61.40 ± 10.70 μM, respectively), and were comparable to or more potent than cisplatin and 5-FU. Also, they were less toxic to normal cells with a higher selectivity index (SI, CCD 841 CoN/HT29 = 4.20 and 2.85, respectively) than reference drugs (SI, CCD 841 CoN/HT29 < 1). Selected Schiff bases were subjected to the P-glycoprotein inhibition assay. Schiff bases 4d, 4e, and 4l influenced P-gp efflux function, significantly increasing the accumulation of rhodamine 123 in colon cancer cell lines. Further mechanistic studies showed that compound 4l induced apoptotic cell death through a caspase-dependent mechanism and by regulating the p53-MDM2 signaling pathway in HT29 cells. Also, physicochemical predictions of compounds 4d, 4e, 4h, and 4i were examined in silico. The results revealed that the compounds possessed promising drug-likeness profiles.

Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions

In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a–l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with K Is in the low nanomolar range (66.60–278.40 nM) than the reference drug acetazolamide (AAZ), which had a K I of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d–g and 5l, with K Is of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, K I of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had K Is ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a K I of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski’s and Jorgensen’s rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents. Communicated by Ramaswamy H. Sarma

Design, synthesis and antifungal activity of novel 1,4-benzoxazin-3-one derivatives containing an acylhydrazone moiety.

A series of 1,4-benzoxazin-3-one derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro antifungal activities against Gibberella zeae, Pellicularia sasakii, Phytophthora infestans, Capsicum wilt, and Phytophthora capsica. The structures of target compounds were characterized by 1H NMR, 13H NMR, 19F NMR and HRMS. The preliminary antifungal evaluation of all target compounds showed that some target compounds possessed moderate to good activities against G. zeae, P. sasakii, P. infestans and C. wilt. Among them, compounds 5L and 5o exhibited noticeable inhibition effects against G. zeae with the EC50 values (effective concentration for 50% activity) of 20.06 and 23.17μg/ml, respectively, which were even nearly double effective than that of hymexazol (40.51μg/ml). Meanwhile, compound 5q displayed a notable inhibitory effect toward P. sasakii, with the EC50 value of 26.66μg/ml, which was better than that of hymexazol (32.77μg/ml). In addition, compound 5r yielded the EC50 value of 15.37μg/ml against P. infestans, which was less than those of hymexazol (18.35μg/ml) and carbendazim (34.41μg/ml). Eventually, compound 5p showed higher inhibitory effect against C. wilt, with EC50 value of 26.76μg/ml, which was better than that of hymexazol (>50μg/ml).

Synthesis and In SilicoStudy of Novel Benzisoxazole-Chromene Derivatives as Potent Inhibitors of Acetylcholinesterase: Metal-Free Site-Selective C-N Bond Formation via Aza-Michael Reaction.

An efficient metal-free approach for site selective C-N coupling reaction of benzo[d]isoxazole and 2H-chromene derivatives has been designed and developed against AchE. This nitrogen containing organo-base promoted methodology, which is both practical and environmentally friendly, provides an easy and suitable pathway for synthesizing Benzisoxazole -Chromene (BC) possessing poly heteroaryl moieties. The synthesized BC derivatives 4a-n was docked into the active sites of AChE to obtain more perception into the binding modes of the compounds. Out of them, compound4a and 4ldisplayed potent activity and high selectivity against the AChE inhibition. Final docking results indicates that compound 4l showed the lowest binding energy of -11.2260 Kcal/mol with AChE. The synthesized BC analogues would be potential candidates for promoting suitable studies in medicinal chemistry research.

Sonochemical synthesis, docking studies and in vitro evaluation of imidazo-1,3-oxazinone derivatives as potential inhibitors of TNF-α

A series of imidazo-1,3-oxazinone derivatives was explored as new and prospective inhibitors of TNF-α. These compounds were synthesized via a direct, one-pot method involving the coupling of appropriate bromo compound with various terminal alkynes in the presence of (PPh3)4Pd, CuI and ZnCl2 in DMF under ultrasound. This sonochemical reaction proceeded via the sequential formation of CC (coupling) and then intramolecular CO bond (cyclization) in the same pot affording the imidazo-1,3-oxazinone derivatives in good yield. A thorough docking studies carried out using the TNF-α protein (PDB: 7JRA and 6 × 81) in silico primarily with the help of AutoDock and then JAMDA docking tool predicted 3j, 3l, 3m and 3o as potential hit molecules from the current series of compounds synthesized. The majority of the compounds interacted with the common interacting residues in the TNF-α trimer e.g. TYR135, TYR227, ILE231, LEU133, LEU233, LEU196 in case of 7JRA and TYR119, TYR59, LEU57, GLY121 in case of 6 × 81. When examined in vitro against TNF-α, the compound 3l, 3m and 3o (with 69–82% inhibition) emerged as the most active compounds in this series. It was observed that the compounds possessing the tricyclic fused ring generally showed better inhibition than that having the fused bicyclic ring as noted during the docking studies. From the viewpoint of SAR (Structure Activity Relationship) the effectiveness of the C-3 aryl group in case of benzoimidazo-1,3-oxazinones was found to be in the order C6H5 > C6H4Me-p > 2-pyridyl > C6H4OMe-p > C6H4Cl-p etc. In terms of IC50 values the compound 3l, 3m and 3o (IC50 ∼5.2–6.2 µM) did not show better activities than rolipram (IC50 ∼0.9 µM) but they appeared to be superior than thalidomide (IC50 ∼197.3 µM). Thus the outcome of docking studies, in vitro evaluation and in silico ADME predictions indicated further pharmacological interest of the preliminary hits identified.

Hybridization of the effective pharmacophores for treatment of epilepsy: design, synthesis, in vivo anticonvulsant activity, and in silico studies of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids

BackgroundEpilepsy is a common neurological disorder. The available drugs for this disease only control convulsions in nearly 70% of patients, while bearing many side effects. In this study, a new series of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids 8a-m was designed, synthesized, and evaluated as potent anticonvulsant agents.MethodsPhenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid derivatives 8a-m were synthesized with well-known chemical reactions and anticonvulsant activity of them was determined by pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid scaffold has the necessary pharmacophores to be a benzodiazepine (BZD) receptor agonist, thus, the most potent anticonvulsant compounds were assayed in vivo and in silico as BZD receptor agonist. Furthermore, in vivo neurotoxicity evaluation and in silico physicochemical, pharmacokinetic, and toxicity study on the most potent compounds were also performed.ResultsObtained results demonstrated that two compounds among the title new compounds have anticonvulsant activity in PTZ test while all of the new compounds are active in the MES test. The best anticonvulsant activities were obtained with nitro derivatives 8k and 8L. In vivo evaluation of flumazenil effect (a BZD receptor antagonist) on anticonvulsant activity of compound 8k confirmed that this compound is a BZD receptor agonist. The most potent compounds 8k and 8L interacted with the important residues of BZD-binding site of GABAA receptor. Furthermore, neurotoxicity of the latter compounds was lower than positive control diazepam.ConclusionAccording to these results, our designed scaffold can be a valuable lead structure for further structural developments and assessments to obtain a new potent anticonvulsant agent.

Green and efficient three-component synthesis of novel isoniazid pyrazoles, molecular docking, antioxidant and antitubercular evaluation

A series of novel isoniazid pyrazole derivatives were synthesized by an efficient, multicomponent reaction of various substituted aromatic aldehydes, isoniazid, and malononitrile in aqueous ethanol. The catalyst-free, green, three-component reaction took place well with good to excellent yields of the desired derivatives. The synthesized novel derivatives were screened for antimicrobial, antioxidant, and anti-TB properties along with the molecular docking study. Some of the synthesized compounds exhibit moderate antibacterial and comparable antifungal properties, while all of them display strong antioxidant activity. The compound 4l demonstrates the most significant activity against M. tuberculosis with MIC = 0.125 µg/mL. The various analytical techniques including FT-IR, 1H NMR, 13C NMR, and HRMS were utilized to confirm the structures of the newly synthesized compounds.

Exploration of quinoxaline-benzimidazole hybrids as apoptosis-inducing agents and tubulin polymerisation inhibitors

We herein report the design and synthesis of a new class of quinoxaline-benzimidazole hybrids based on the molecular hybridization concept and evaluation of their in vitro cytotoxicity profile against human cancer cell lines, i.e., colorectal, lung, skin, and mouse melanoma cell line. Among all the screened compounds, compound 5l (2-(1-(3, 4-dichlorobenzyl)-1H-benzo[d]imidazol-2-yl)quinoxaline) exhibited potent cytotoxicity against lung cancer cell line (A549) with an IC50 of 4.37 ± 0.09 µM with a cytospecificity towards cancer cells. Further, AO/EB, DAPI, DCFDA, and JC-1 staining techniques confirmed that 5l induced apoptosis in the A549 cell line. In addition, 5l in annexin V-FITC/PI assay induced early apoptosis. The clonogenic assay revealed that 5l inhibited colony formation in a dose-dependent manner. Cell cycle distribution analysis unveiled that 5l caused the arrest of G2/M phase of cell cycle. Moreover, 5l inhibited tubulin polymerization with an IC50 value of < 2.19 µM. Docking studies revealed that 5l has a prominent binding affinity towards colchicine binding site of α/β- tubulin with good protein-ligand interactions with a binding energy of -45.139 kcal/mol. In silico ADME/T prediction studies disclosed the favourable drug-like properties of 5l.

Electrochemical Synthesis of New Isoxazoles and Triazoles Tethered with Thiouracil Base as Inhibitors of Histone Deacetylases in Human Breast Cancer Cells

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.