Tailored Tetrasubstituted Imidazole Carrying the Benzenesulfonamide Fragments as Selective Human Carbonic Anhydrase IX/XII Inhibitors.

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5 a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for in-vitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5 d, 5 g, and 5 l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX) showed the best inhibitory profile. In-vitro screening of all derivatives against a full sixty-cell-lined from NCI at a single dose of 10 µM offered growth inhibition of up to 45 %. Compound 5 b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor-related hCAs IX/XII suppression.

Isolation and in silico investigation of cannflavins from Cannabis sativa leaves as potential anti-SARS-CoV-2 agents targeting the Papain-Like Protease.

This study aimed to isolate and identify three prenylflavonoids (cannflavin A, B, and C) from Cannabis sativa leaves using different chromatographic techniques. The potential of the isolated compounds against SARS-CoV-2 was suggested through several in silico analysis. Structural similarity studies against nine co-crystallized ligands of SARS-CoV-2's proteins indicated the similarities of the isolated cannflavins with the SARS-CoV-2 Papain-Like Protease (PLP) ligand, Y95. Then, flexible allignment study confirmed this similarity. Docking experiments showed successful binding of all cannflavins within the active pocket of PLP, with energies comparable to Y95. Among them, cannflavin A demonstrated the most similar binding mode, while cannflavin C exhibited the best energy. Molecular dynamics (MD) simulations and MM-GPSA confirmed the accurate binding of cannflavin A to the PLP. In silico ADMET studies indicated favourable drug-like properties for all three compounds, suggesting their potential as anti-SARS-CoV-2 agents. Further In vitro and In vivo investigations are necessary to validate these findings and establish their efficacy and safety profiles.

Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a-j, 8a-j, 9a-c, and 10a-c. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.

Design, synthesis, cytotoxic activities, and molecular docking of chalcone hybrids bearing 8-hydroxyquinoline moiety with dual tubulin/EGFR kinase inhibition.

The present study established thirteen novel 8-hydroxyquinoline/chalcone hybrids3a-mof hopeful anticancer activity. According to NCI screening and MTT assay results, compounds3d-3f, 3i,3k,and3ldisplayed potent growth inhibition on HCT116 and MCF7 cells compared to Staurosporine. Among these compounds,3eand3fshowed outstanding superior activity against HCT116 and MCF7 cells and better safety toward normal WI-38 cells than Staurosporine. The enzymatic assay revealed that3e,3d, and3ihad goodtubulin polymerization inhibition (IC50 = 5.3, 8.6, and 8.05 µM, respectively) compared to the reference Combretastatin A4 (IC50 = 2.15 µM). Moreover,3e,3l, and3fexhibited EGFR inhibition (IC50 = 0.097, 0.154, and 0.334 µM, respectively) compared to Erlotinib (IC50 = 0.056 µM). Compounds3eand3fwere investigated for their effects on the cell cycle, apoptosis induction, andwnt1/ß-cateningene suppression. The apoptosis markers Bax, Bcl2, Casp3, Casp9, PARP1, and ß-actin were detected by Western blot. In-silico molecular docking, physicochemical, and pharmacokinetic studies were implemented for the validation of dual mechanisms and other bioavailability standards. Hence, Compounds3eand3fare promising antiproliferative leads with tubulin polymerization and EGFR kinase inhibition.

Anticancer Activities of Tetrasubstituted Imidazole-Pyrimidine-Sulfonamide Hybrids as Inhibitors of EGFR Mutants.

A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores has been synthesized and evaluated for their anticancer activities. In-vitro screening of these hybrids against a full 60-cell-line panel at a single dose of 10 µM showed significant growth inhibition of up to 95 %. The most active compound showed in-vitro anticancer activities against (i) abnormal HER2 and (ii) two mutants for EGFR. Apoptotic gene expression revealed that lead compounds induced MCF-7 cell line apoptosis together with considerable change in the Bax/Bcl-2 expression ratio. One lead compound led to a significant cell-cycle S-phase arrest, while another blocked the cell cycle at G1/S-phase causing the accumulation of cells. Docking analysis of these two hybrids adopted the orientation and binding interactions with a higher liability to enter the active side pocket of HER2, L858R, and T790 M, preferable to that of co-crystallized ligands. Modelling simulation was consistent with the acquired biological evaluation.

A Polymer-based Monolithic Capillary Column with Polymyxin-B Chiral Selector for the Enantioselective Nano-High Performance Liquid Chromatographic Pharmaceutical Analysis.

Herein, we report the first use of Polymyxin-B antibiotic as a enantio-selector in polymer monolithic capillary. The capillaries were functionalised, characterized and tested for the enantioselective nano-HPLC separation of 50 racemic pharmaceutical drugs. They have been easily prepared by immobilizing Polymyxin-B over the organic polymer for 48 h (P1) or encapsulating Polymyxin-B within the organic polymer (P2) and tested for the enantioselective resolution of racemic drugs. Acceptable resolution was achieved for 21 drugs using RP-HPLC conditions on both (P1) and (P2) capillary columns, while no separation was observed under NP-HPLC conditions. Polymyxin-B is commercially available, easily solubilized and stable in both acidic and neutral media. The developed Polymyxin-B-based polymer monolithic capillaries provide a promising expansion of platform in enantioselective HPLC separations.

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Fluorinated Candidates as PI3K Inhibitors: Targeting Fluorophilic Binding Sites.

Highly fluorinated candidates containing anticancer pharmacophores like thiosemicarbazone (5a-e) and its cyclic analogues hydrazineylidenethiazolidine (6a-e), 2-aminothiadiazole (7a-e), and 2-hydrazineylidenethiazolidin-4-one (8a-e) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds 6c, 7b, and 8b displayed the most potent activity with lower toxic effects on MCF-10a. In vitro phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound 6c displayed half-maximal inhibitory concentration (IC50, µM) values of 5.8, 2.3, and 7.9; compound 7b displayed IC50 values of 19.4, 30.7, and 73.7; and compound 8b displayed IC50 values of 77.5, 53.5, and 121.3 for PI3Kα, ß, and δ, respectively. Moreover, cell cycle progression caused cell cycle arrest at the S phase for compounds 6c and 8b and at G1/S for compound 7b, while apoptosis was induced. In silico studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 6c is the most potent one with a selectivity index (SI) of 39 and is considered as a latent lead for further optimization of anticancer agents.

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors.

A novel series of tri-aryl imidazole derivatives 5a-n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3-1.3 µM, and selectivity ratio for hCA IX over hCA XII = 5-12) relative to acetazolamide (Ki = 0.03 µM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI50 = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI50 = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.

Synthesis, DFT Calculations, Antiproliferative, Bactericidal Activity and Molecular Docking of Novel Mixed-Ligand Salen/8-Hydroxyquinoline Metal Complexes.

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2'-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, 1H NMR, 13C NMR, UV-VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H2O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H2O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC50 values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC50 values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature.

Daptomycin: A Novel Macrocyclic Antibiotic as a Chiral Selector in an Organic Polymer Monolithic Capillary for the Enantioselective Analysis of a Set of Pharmaceuticals.

Daptomycin, a macrocyclic antibiotic, is here used as a new chiral selector in preparation of chiral stationary phase (CSP) in a recently prepared polymer monolithic capillary. The latter is prepared using the copolymerization of the monomers glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in the presence of daptomycin in water. Under reversed phase conditions (RP), the prepared capillaries were tested for the enantioselective nanoliquid chromatographic separation of fifty of the racemic drugs of different pharmacological groups, such as adrenergic blockers, H1-blockers, NSAIDs, antifungal drugs, and others. Baseline separation was attained for many drugs under RP-HPLC. Daptomycin expands the horizon of chiral selectors in HPLC.

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors.

A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1H NMR, 13C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1-21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2-6, oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans, ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC50 of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC50 = 170 nM). Compounds 4, 5, and 6 showed IC50 values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC50 = 11 µM).

Design, synthesis, biological evaluation, and computational studies of novel thiazolo-pyrazole hybrids as promising selective COX-2 inhibitors: Implementation of apoptotic genes expression for ulcerogenic liability assessment.

A novel series of thiazolo-pyrazole hybrids has been prepared and assessed for their in vitro COX-1/COX-2 inhibitory activity. Compound 6c exhibited the most selective COX-2 inhibition profile (SI of 264) not far of Celecoxib (294). In-vivo anti-inflammatory activity revealed that compound 6d exhibited the highest activity (97.30% inhibition of edema) exceeding reference standard Indomethacin (84.62% inhibition of edema). The ulcerogenic liability tested, using gross, microscopic, biochemical analysis and apoptotic genes expression, showed that compound 6b matched the optimal candidate activity (ulcer index = 120, selectivity index of ~ 162 and 77% in-vivo inhibition of edema). Meanwhile, compound 6 m (ulcer index = 0) showcased the highest safety profile. Molecular modeling analysis and drug likeness studies presented appreciated agreement with the biological evaluation.

JNK signaling as a target for anticancer therapy.

The JNKs are members of mitogen-activated protein kinases (MAPK) which regulate many physiological processes including inflammatory responses, macrophages, cell proliferation, differentiation, survival, and death. It is increasingly clear that the continuous activation of JNKs has a role in cancer development and progression. Therefore, JNKs represent attractive oncogenic targets for cancer therapy using small molecule kinase inhibitors. Studies showed that the two major JNK proteins JNK1 and JNK2 have opposite functions in different types of cancers, which need more specification in the design of JNK inhibitors. Some of ATP- competitive and ATP non-competitive inhibitors have been developed and widely used in vitro, but this type of inhibitors lack selectivity and inhibits phosphorylation of all JNK substrates and may lead to cellular toxicity. In this review, we summarized and discussed the strategies of JNK binding inhibitors and the role of JNK signaling in the pathogenesis of different solid and hematological malignancies.

Structure-based design, synthesis, and biological evaluation of novel piperine-resveratrol hybrids as antiproliferative agents targeting SIRT-2.

A series of novel piperine-resveratrol hybrids 5a-h was designed, synthesized, and structurally elucidated by IR, and 1H, 13C, and 19F NMR. Antiproliferative activities of 5a-h were evaluated by NCI against sixty cancer cell lines. Compound 5b, possessing resveratrol pharmacophoric phenolic moieties, showed a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth inhibition percentage of -0.49 and -2.83, respectively. In addition, 5b recorded significant activity against the other cancer cell lines with growth inhibition percentage between 80 to 95. New 5a-h hybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their antiproliferative action. Results showed that compounds 5a-h were more potent inhibitors of Sirt-2 than Sirt-1 at 5 µm and 50 µm. Compound 5b showed the strongest inhibition of Sirt-2 (78 ± 3% and 26 ± 3% inhibition at 50 µM and 5 µM, respectively). Investigation of intermolecular interaction via Hirschfeld surface analysis indicates that these close contacts are mainly ascribed to the O-H⋯O hydrogen bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where 5b was found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with the substrate acyl-Lys. Another possible binding pattern showed that 5b could act by partial occlusion of the NAD+ C-pocket. Collectively, these findings would contribute significantly to better understanding the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2 inhibitors.

Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies.

Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041-0.081 µM, SI 139.74-321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3-48.3, 1 h; 58.4-60.5, 2 h; 70.8-83.2, 3 h; 78.9-89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.

Design, synthesis and antiproliferative evaluation of new tricyclic fused thiazolopyrimidines targeting topoisomerase II: Molecular docking and apoptosis inducing activity.

A novel series of thiazolopyrimidines and fused thiazolopyrimidines was designed and synthesized as topoisomerase II alpha inhibitors. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compound 3a was found to be the most potent inhibitor on renal cell line (A-498) causing 83.03% inhibition (IC50 = 1.89 µM). DNA-flow cytometric analysis showed that compound 3a induce cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Moreover, fused thiazolopyrimidines 3a showed potent topoisomerase II inhibitory activity (IC50 = 3.19 µM) when compared with reference compound doxorubicin (IC50 = 2.67 µM). Docking study of all the synthesized compounds showed that compound 3a interacts in a similar pattern to etoposide and stabilizing the topoisomerase cleavage complex (Top2-cc) that accounts for its high potency.

Design, synthesis and molecular modeling of novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles derived from indomethacin as potent anti-inflammatory iNOS/PGE2 inhibitors.

The development of NSAIDs/iNOS inhibitor hybrids is a new strategy for the treatment of inflammatory diseases by suppression of the overproduction of PGE2 and NO. A novel series of aryl carboximidamides 4a-g and their cyclized 3-aryl-1,2,4-oxadiazoles 5a-g counterparts derived from indomethacin 1 were synthesized. Most of the target compounds displayed lower LPS-induced NO production IC50 in RAW 264.7 cells and potent in vitro iNOS and PGE2 inhibitory activity than indomethacin. Moreover, in carrageenan-induced rat paw oedema method, most of them exhibited higher in vivo anti-inflammatory activity than the reference drug indomethacin. Notably, 4 hrs after carrageenan injection, compound 4a proved to be the most potent anti-inflammatory agent in this study, with almost two- and eight-fold more active than the reference drugs indomethacin (1) and celecoxib, respectively. Compound 4a proved to be inhibitor to LPS-induced NO production, iNOS activity and PGE2 with IC50 of 10.70 µM, 2.31 µM, and 29 nM; respectively. Compounds 4a and 5b possessed the lowest ulcerogenic liabilities (35% and 38%, respectively) compared to 1. Histopathological analysis revealed that compounds 4a and 5b demonstrated reduced degeneration and healing of ulcers. Molecular docking studies into the catalytic binding pocket of the iNOS protein receptor (PDB ID: 1r35) showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and ADMET analysis were calculated where compound 4a had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed anti-inflammatory therapy and entitled to be used as future template for further investigations.

Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation.

A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI50 ranging from 19 to 100 µM and selectivity ratios ranging between 0.75 and 1.71 at the GI50 level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC50 = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of -9.80 to -11.25 kcal/mol compared to -12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e.

Design, synthesis and anticonvulsant activity of new imidazolidindione and imidazole derivatives.

New imidazolidindiones and tetra-substituted imidazole derivatives were designed, synthesized, and evaluated for the anticonvulsant activity through pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) tests using valproate sodium and phenytoin sodium as reference drugs, respectively. Most of the target compounds showed excellent activity against pentylenetetrazole (PTZ)-induced seizures with fair to no-activity against MES. Compounds 3d, 4e, 11b, and 11e showed higher activity (120%) than that of valproate sodium in PTZ model. Almost all compounds showed no neurotoxicity, as indicated by the rotarod test. Estimation of physicochemical properties and pharmacokinetic profiles of the target compounds were studied. The chemical structures of the target compounds were characterized by different spectrometric methods and elemental analysis.

Design, synthesis and antitrypanosomal activity of heteroaryl-based 1,2,4-triazole and 1,3,4-oxadiazole derivatives.

Two series of novel 1,2,4-triazol-3-yl-thioacetamide 3a-b and 4a-b and 5-pyrazin-2-yl-3H-[1,3,4]oxadiazole-2-thiones 9a-h were designed and synthesized. The compounds prepared have been identified using 1H NMR, 13C NMR and elemental analyses. The synthesized compounds 3a, 3b, 4a, 4b, 9a, 9b, 9d-e and 9f have been evaluated with α-difluoromethylornithine (DFMO) as a control drug for their in vitro antitrypanosomal activity against Trypanosoma brucei. Results showed that 3b was the most active compound in general and also more potent than control DFMO. 3b was 8 folds more potent than the reference with IC50 of 0.79 µM and IC90 of 1.35 µM, respectively compared to DFMO (IC50 = 6.10 µM and IC90 of 8.66 µM). The tested compounds showed moderate cytotoxicity with selectivity indices ranging from 12 (9d) to 102 (3b) against L6 cells. Docking study was performed into ten of T. brucei enzymes which have been identified as potential/valid targets for most of the antitrypanosomal agents. The results of the docking study revealed high binding scores toward many of the selected enzymes. A good correlation was observed only between log (IC50) of antitrypanosomal activity of the new compounds and their calculated Ki values against TryR enzyme (R2 = 0.726). Compound 3b, the most active as antitrypanosomal agents exhibited similar binding orientation and interaction to those of WP6 against TryR enzyme. However, in a next round of work, a complementary studies will be carried out to clarify the mechanism of action of these compounds.