Design, synthesis, biological evaluation and docking study of some new aryl and heteroaryl thiomannosides as FimH antagonists.

FimH is a mannose-recognizing lectin that is expressed by Escherichia coli guiding its ability to adhere and infect cells. It is involved in pathogenesis of urinary tract infections and Chron's disease. Several X-ray structure-guided ligand design studies were extensively utilized in the discovery and optimization of small molecule aryl mannoside FimH antagonists. These antagonists retain key specific interactions of the mannose scaffolds with the FimH carbohydrate recognition domains. Thiomannosides are attractive and stable scaffolds, and this work reports the synthesis of some of their new aryl and heteroaryl derivatives as FimH antagonists. FimH-competitive binding assays as well as biofilm inhibition of the new compounds (24-32) were determined in comparison with the reference n-heptyl α-d-mannopyranoside (HM). The affinity among these compounds was found to be governed by the structure of the aryl and heteroarylf aglycones. Two compounds 31 and 32 revealed higher activity than HM. Molecular docking and total hydrophobic to topological polar surface area ratio calculations attributed to explain the obtained biological results. Finally, the SAR study suggested that introducing an aryl or heteroaryl aglycone of sufficient hydrophobicity and of proper orientation within the tyrosine binding site considerably enhance binding affinity. The potent and synthetically feasible FimH antagonists described herein hold potential as leads for the development of sensors for detection of E. coli and treatment of its diseases.

Neuroprotective effects of rutin against cuprizone-induced multiple sclerosis in mice.

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal degeneration and functional impairments. No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL/6 mice by dietary 0.2% (w/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100 mg/kg) or DMF (15 mg/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ + RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-κB at the binding site of the protein-DNA complex, with a good negative score of -6.79 kcal/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1-Nrf2 protein-protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-κB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.

Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.

Design, Synthesis, and Biological Evaluation of Indole-2-carboxamides as Potential Multi-Target Antiproliferative Agents.

A small set of indole-based derivatives, IV and Va-I, was designed and synthesized. Compounds Va-i demonstrated promising antiproliferative activity, with GI50 values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives-Va, Ve, Vf, Vg, and Vh-were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC50 value of 71 ± 06 nM, which is higher than the reference erlotinib (IC50 = 80 ± 05 nM). Compounds Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib's IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAFV600E, and VEGFR-2.

Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action.

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four cancer cell lines tested, with mean GI50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors.

Design, synthesis, apoptotic, and antiproliferative effects of 5-chloro-3- (2-methoxyvinyl)-indole-2-carboxamides and pyrido[3,4-b]indol-1-ones as potent EGFRWT/EGFRT790M inhibitors.

A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c, 5d, 5f, 5 g, 6e, and 6f have the highest antiproliferative activity with GI50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFRT790M with IC50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFRWT and EGFRT790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.

Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-indole-2-carboxylate and Pyrrolo[3,4-b]indol-3-one Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways.

Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a-e, 4a-c and pyrrolo[3,4-b]indol-3-ones 5a-c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of 3a-e, 4a-c, and 5a-c revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds 3a-e, 4a-c, and 5a-c had significant antiproliferative activity with GI50 values ranging from 29 nM to 78 nM, with 3a-e outperforming 4a-c and 5a-c in their inhibitory actions against the tested cancer cell lines. Compounds 3a-e were tested for EGFR inhibition, with IC50 values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a-e had higher anti-BRAFV600E activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a-e revealed safety and good pharmacokinetic profile.

Phytochemical investigation, molecular docking studies and DFT calculations on the antidiabetic and cytotoxic activities of Gmelina philippensis CHAM.

ETHNOPHARMACOLOGICAL RELEVANCE: Gmelina philippensis CHAM is an ornamental plant that is distributed in South Asia and warm regions of the Mediterranean area. The plant is traditionally applied in folk medicine for the treatment of diabetes. AIM OF THE STUDY: To evaluate the cytotoxic and the antidiabetic activities of the ethanolic extract of G. philippensis aerial parts. To isolate the metabolite(s) responsible for these activities and to elucidate the mechanism of action by molecular docking study. MATERIALS AND METHODS: Compounds (1-11) were isolated using various chromatographic techniques and their structures were determined by NMR spectroscopic and mass spectrometric analysis. The cytotoxic effect was tested using viability test and MTT assay. Antidiabetic activity was evaluated by measuring the inhibitory activity of the ethanolic extracts and compounds against α-glucosidase and α-amylase activities. Modeling and docking simulations were performed using Molecular Operating Environment software and the crystal structure of protein kinases CDK2, (1PYE) and AKT1 (4GV1), in addition to α-glucosidase (3TOP) and α-amylase (2QV4). RESULTS: Compounds 2, 3 and 8 were isolated for the first time from the plant and identified as: gmelinol (2), apigenin (3) and tyrosol (8). While ß-sitosterol-3-O- ß-D-glucopyranoside (4) vicenin-II (7), rhoifolin (9), isorhoifolin (11) were isolated for the first time from the genus, along with and the new iridoid 6-O-α-L-(2″-O-benzoyl-4″-O-trans-p-methoxycinnamoyl)rhamnopyranosyl-1α- ß-D-glucopyranoside catalpolgenin (6). In addition, to the previously reported compounds: mixture of ß -sitosterol and stigmasterol (1), and 6- O- α-L-(2″,3″,4″-tri-O -benzoyl)rhamnopyranosylcatalpol (5) and 6-O-α-L-(2″-O-trans-p-methoxycinnamoyl)rhamnopyranosylcatalpol (10). The cytotoxic activity against hepatocellular carcinoma (HepG-2) cell lines for compounds 2, 5, 7, 9 and 11 was conducted using cisplatin as a standard. Gmelinol (2) exhibited strong cytotoxic activity against HepG-2 cell lines with IC 50 value of 3.6 ± 0.1 µg/ml which is more potent than the standard cisplatin IC 50 = 8.7 ± 0.9 µg/ml. Molecular modeling of 2 against diverse targets of protein kinases suggested that CDK-2 and AKT-1 could be the dual probable kinase targets for its cytotoxic action. Compound 2 showed α-amylase inhibition activity with IC 50 value of 60.9 (µg/ml) while, compounds 5 showed strong α-glucosidase inhibition activity with IC 50 values of 41.7 (µg/ml) compared to acarbose with IC 50 value of 34.7, 30.6 (µg/ml). Molecular docking of compounds 2 and 5 on α-glucosidase (3TOP) and α-amylase (2QV4) enzymes revealed high binding affinity and active site interactions comparable to native ligand acarbose. CONCLUSION: The ethanolic extract of G. philippensis CHAM aerial parts is effective against HepG-2 cell lines, α-amylase and α-glucocidase activities. Biologically guided isolation indicated that compounds 2 and 5 are responsible for these activities. These results were supported by DMF calculations that detected the molecular areas responsible for protein interactions shown via docking studies.

New 1,3,4-oxadiazoles linked with the 1,2,3-triazole moiety as antiproliferative agents targeting the EGFR tyrosine kinase.

A series of 1,3,4-oxadiazole-1,2,3-triazole hybrids bearing different pharmacophoric moieties has been designed and synthesized. Their antiproliferative activity was evaluated against four human cancer cell lines (Panc-1, MCF-7, HT-29, and A-549) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The preliminary activity test displayed that the most active compounds, 6d, 6e, and 8a-e, suppressed cancer cell growth (GI50 = 0.23-2.00 µM) comparably to erlotinib (GI50 = 0.06 µM). Compounds 6d, 6e, and 8a-e inhibited the epidermal growth factor receptor tyrosine kinase (EGFR-TK) at IC50 = 0.11-0.73 µM, compared to erlotinib (IC50 = 0.08 ± 0.04 µM). The apoptotic mechanism revealed that the most active hybrid 8d induced expression levels of caspase-3, caspase-9, and cytochrome-c in the human cancer cell line Panc-1 by 7.80-, 19.30-, and 13-fold higher than doxorubicin. Also, 8d increased the Bax level by 40-fold than doxorubicin, along with decreasing Bcl-2 levels by 6.3-fold. Cell cycle analysis after treatment of Panc-1 cells with hybrid 8d revealed a high proportion of cell accumulation (41.53%) in the pre-G1 phase, indicating cell cycle arrest at the G1 transition. Computational docking of the 8d and 8e hybrids with the EGFR binding site revealed their ability to bind with EGFR similar to erlotinib. Finally, in silico absorption, distribution, metabolism, and excretion/pharmacokinetic studies for the most active hybrids are discussed.

Anti-inflammatory and cytotoxic specialised metabolites from the leaves of Glandularia × hybrida.

In our ongoing effort to investigate active specialised metabolites from genus Glandularia, phytochemical studies on the ethanolic extract of Glandularia × hybrida (Groenl. & Rümpler) G.L. Nesom & Pruski leaves resulted in the isolation of three undescribed compounds, a dibenzylbutyrolactolic lignan and two echinocystic acid based triterpenoid saponins, in addition to two known compounds. Interestingly, this study reports isolation of chemo-systematically valuable specialised metabolites for the first time from the genus under investigation. Additionally, the isolated metabolites were evaluated for their iNOS inhibition and cytotoxic activities using a combination of in silico and in vitro studies. The pharmacokinetics properties (ADMET) of some of the isolated compounds were determined using pkCSM-pharmacokinetics server. Molecular docking analysis showed that saponin compound possesses higher negative score (-9.59 kcal/mol) than the lignan compound (-6.56 kcal/mol). The isolated compounds also showed iNOS inhibition activity with IC50 values ranging between 6.6 and 49.7 µM and significant cytotoxic activity against a series of cell lines including SK-MEL, KB, BT-549, SK-OV-3, LLC-PK1 and VERO cells. Hence, this study reveals that specialised metabolites from G. hybrida plant are of significant anti-inflammatory and cytotoxicity potentials.

Cytotoxic and anti-diabetic potential, metabolic profiling and insilico studies of Syzygium cumini (L.) Skeels belonging to family Myrtaceae.

LC-HR-MS-coupled metabolic profiling of the methanol extracts from different parts of Syzygium cumini (L.), which was extensively identified via DNA fingerprinting, led to dereplication of 24 compounds. Cytotoxic investigation highlighted both extracts as the most potent, against both MCF-7 and MDA-231 Cell lines, with IC50 value of 5.86 ± 0.63 µg/ml and against HCT -116 cell line, with IC50 value of 1.24 ± 0.09 µg/ml, respectively. A molecular docking study was performed on the dereplicated compounds, which highlighted myricetin-3-glucoside (7), myricitrin (12), reynoutrin (15) and quercitrin (16) as the top scoring ligands within the protein active site (FIH-1). Interestingly, the extracts were significant against streptozotocin-induced diabetes in the order of flowers > seeds > leaves with BGL level of 98.9 ± 4.3, 123.2 ± 4.9 and 132.8 ± 5.9 mg/dl, respectively. The study highlights the health benefits of Syzygium cumini (L.) as a promising cytotoxic source.

Potential of (Citrus nobilis Lour × Citrus deliciosa Tenora) metabolites on COVID-19 virus main protease supported by in silico analysis.

One of the promising therapeutic strategies for corona virus 2019 (COVID-19) is tolook for enzyme inhibitors. COVID-19 virus main protease (Mpro) plays a vital role in mediating viral transcription and replication, introducing it as an attractive antiviral agent target. LC-ESI-HDMS based metabolic profiling of Citrus nobilis Lour. × Citrus deliciosa Ten. (Rutaceae) annotated 21 compounds belonging to diverse classes. Molecular docking studies were carried out to ascertain the inhibitory action of studied dereplicated compounds through the interactions within the active site of SARS-CoV-2 (Mpro). Among which, quercetin-7-O-glucoside-3-O-rutinoside (21) possessed the best binding affinity (-9.47 kcal/mol), followed by luteoline-7-rutinoside (18), quercetin-3-O-rutinoside (19) and apigenin-8-C-glucoside (15) showed less binding affinities ranging at -8.27, -7.97 and -6.94 kcal/mol respectively.

The inhibition of inducible nitric oxide production in lipopolysaccharide-stimulated rat macrophages and in silico studies by flavonoids from Iris spuria L. rhizomes.

ETHNOPHARMACOLOGICAL RELEVANCE: Iris is the largest genus in the family Iridaceae. Iris plants are distributed in tropical regions of the world. They are used as ornamentals and traditionally used to treat a variety of ailments. AIM: This study aimed to evaluate the anti-inflammatory effect of flavonoids isolated from Iris spuria L. MATERIALS AND METHODS: The isolated flavonoids (1-4) were identified on the basis of different spectroscopic methods (1D- and 2D-NMR) and co-TLC with authentic samples. The anti-inflammatory effect was tested on lipopolysaccharide (LPS)-induced nitric oxide (NO) production from rat-isolated peritoneal macrophages. Modeling and docking simulations of the compounds were performed using Molecular Operating Environment software and the crystal structure of the murine inducible nitric oxide synthase (iNOS). RESULTS: Four flavonoids (1-4) had been isolated from the rhizomes of Iris spuria L. (Hocka Hoona) for the first time. They were characterized as 5,7,2'-trihydroxy-6-methoxyflavanone (1), tectorigenin 7-O-ß-D-glucopyranoside (2), tectorigenin 4'-O-ß-D-glucopyranoside (3), and tectorigenin 4'-O-[ß-D-glucopyranosyl(1 â†’ 6)-ß-D-glucopyranoside] (4). The selective inducible NO synthase inhibitor; aminoguanidine was used as a positive control. The production of nitric oxide (NO) was inhibited in a dose-dependent manner of the isolated compounds along with isoflavonoids (5-9) previously isolated from Iris spuria L. (Calizona). A concentration of 60 µg/ml of all tested compounds showed a significant inhibitory effect compared to media with LPS. Molecular modeling experiments supported the obtained biological data. CONCLUSION: Our results reveal that flavonoids isolated from I. spuria L. (Hocka Hoona) and I. spuria L. (Calizona) appear to have a potential anti-inflammatory effect via inhibition of iNOS.

New Cytotoxic Natural Products from the Red Sea Sponge Stylissa carteri.

Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (1), and a cerebroside, stylissoside A (2), from the methanol extract of the Red Sea sponge Stylissa carteri. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract's metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, 1 and 2, displayed strong cytotoxicity against the MCF-7 cell line, with IC50 values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC50 at 36.8 ± 0.16 µM for 1 and IC50 30.5 ± 0.23 µM for 2 compared to the standard drug cisplatin. Molecular docking experiments showed that 1 and 2 displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents.

Click chemistry synthesis, biological evaluation and docking study of some novel 2'-hydroxychalcone-triazole hybrids as potent anti-inflammatory agents.

A hybrid pharmacophore approach is used to design and synthesize two novel series of 2'-hydroxychalcone-triazole hybrid molecules 6a-j and 8a-j. These compounds were fully characterized by spectral and elemental analyses. They were evaluated in vitro and in vivo for anti-inflammatory activity. Most of compounds were selective inhibitors for COX-2. Among them, compounds 6d, 6f, 6i, 8c, 8e and 8h demonstrated highly potent dual inhibition of COX-2 (IC50 = 0.037-0.041 µM) and 15-LOX (IC50 = 1.41-1.80 µM). Compounds 6i, 8c and 8h showed 116%, 113% and 109% of the in vivo anti-inflammatory activity of celecoxib. Therefore, compounds 6d, 6f, 6i, 8c, 8e and 8h-j are potent dual inhibitors of COX-2 and 15-LOX. Docking study over COX-2 and 15-LOX active sites ensures the binding affinity and selectivity. These compounds are promising candidates for further development as anti-inflammatory drugs.

Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives.

A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C6H4) displayed good inhibitory activity (HSV-1 EC50 1.5 µM, HSV-2 EC50 0.8 µM) and retained inhibitory activity in HSV-1 TK- cells (EC50 0.8 µM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds.

Design, synthesis and molecular docking of some new 1,2,4-triazolobenzimidazol-3-yl acetohydrazide derivatives with anti-inflammatory-analgesic activities.

The present work describes the synthesis and evaluation of some new acetohydrazones, 1,3,4-oxadiazoles and 1,2,4-triazoles of 1,2,4-triazolo[1,5-a]benzimidazole as anti-inflamm atory-analgesic agents. Structure elucidation of these compounds was confirmed by IR, (1)H NMR, and mass spectrometry along with elemental microanalyses. Most compounds exhibited significant anti-inflammatory activity in comparison to indomethacin. Further, some compounds were tested for their analgesic effects where two compounds showed results comparable to indomethacin at 4 h interval. The most active anti-inflammatory and analgesic compounds (4c and 11a) were examined on gastric mucosa and didn't show any gastric ulcerogenic effect compared with the reference indomethacin. Moreover, LD50 of compounds (4c and 11a) were determined in mice; they were found non toxic up to 240 and 300 mg/kg (i.p.). Also, docking simulation of some compounds into COX active sites was studied.