Synthesis and evaluation of larvicidal efficacy against C. pipiens of some new heterocyclic compounds emanated from 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide.

Several infectious diseases are transmitted and spread by mosquitoes, and millions of people die annually from them. The mosquito, Culex pipiens is a responsible for the emergence of various Virus in Egypt. So, we devote our work to evaluate the larvicidal efficacy against C. pipiens of some new heterocyclic compounds containing chlorine motifs. The implementation was emanated from using 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (3) as scaffold to synthesize some new heterocyclic compounds. The structures of the synthesized compounds were interpreted scrupulously by spectroscopic and elemental analyses. Thereafter, the larvicidal activity against C. pipiens of thirteen synthesized compounds was estimated. Noteworthy, cyanoacetohydrazide derivative 3 and 3-iminobenzochromene derivative 12 showed a fabulous potent efficacy with LC50 equal to 3.2 and 3.5 ppm against C. pipiens, respectively, and are worth being further evaluated in the field of pest control.

New pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors: design, green synthesis, potential anti-proliferative activity and P-glycoprotein inhibition.

In this study, four series of new pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized with both green and conventional methods. All the synthesized candidates were chemically confirmed using spectroscopic methods, and the DFT of the reaction mechanism was illustrated. The anti-proliferative activity of the synthesized compounds was evaluated against NCI 60 cancer cell lines. Two compounds (15 & 16) exhibited excellent broad-spectrum cytotoxic activity in NCI 5-log dose assays against the full 60-cell panel with GI50 values ranging from 0.018 to 9.98 µM. Moreover, the enzymatic assessment of the most active derivatives 4, 15, and 16 against EGFR tyrosine kinase showed significant inhibitory activities with IC50 of 0.054, 0.135, and 0.034 µM, respectively. The quantitative real-time PCR for the P-glycoprotein effect of compounds 15 and 16 was examined and illustrated the ability to inhibit the P-glycoprotein by 0.301 and 0.449 fold in comparison to the control. Mechanistic study using reversal activity in MDA-MB-468 cell line revealed the effect of both compounds 15 and 16 cytotoxicity against DOX/MDA-MB-468 with IC50 = 0.267 and 0.844 µM, respectively. Additionally, compound 16 was found to induce cell cycle arrest at the S phase with a subsequent increase in pre-G cell population in MDA-MB-468 cell line. It also increased the percentage of apoptotic cells in a time-dependent manner. Moreover, a molecular docking study was carried out to explain the target compounds' potent inhibitory activity within the EGFR binding site.

Optimal sampling and statistical inferences for Kumaraswamy distribution under progressive Type-II censoring schemes.

In this paper, we study non-Bayesian and Bayesian estimation of parameters for the Kumaraswamy distribution based on progressive Type-II censoring. First, the maximum likelihood estimates and maximum product spacings are derived. In addition, we derive the asymptotic distribution of the parameters and the asymptotic confidence intervals. Second, Bayesian estimators under symmetric and asymmetric loss functions (Squared error, linear exponential, and general entropy loss functions) are also obtained. The Lindley approximation and the Markov chain Monte Carlo method are used to derive the Bayesian estimates. Furthermore, we derive the highest posterior density credible intervals of the parameters. We further present an optimal progressive censoring scheme among different competing censoring scheme using three optimality criteria. Simulation studies are conducted to evaluate the performance of the point and interval estimators. Finally, one application of real data sets is provided to illustrate the proposed procedures.

Radiation Synthesis of Carbon/Aluminum/Silica Aerogel Nanoporous Structure Derived from Polyacrylamide Hydrogel for High Temperature and Oil Removal Applications.

Aerogel is a high-performance thermal resistance material desired for high-temperature applications like dye-sensitized solar cells, batteries, and fuel cells. To increase the energy efficiency of batteries, an aerogel is required to reduce the energy loss arising from the exothermal reaction. This paper synthesized a different composition of inorganic-organic hybrid material by growing the silica aerogel inside a polyacrylamide (PAAm) hydrogel. The hybrid PaaS/silica aerogel was synthesized using different irradiation doses of gamma rays (10-60 kGy) and different solid contents of PAAm (6.25, 9.37, 12.5, and 30 wt %). Here, PAAm is used as an aerogel formation template and carbon precursor after the carbonization process at a temperature of (150, 350, and 1100 °C). The hybrid PAAm/silica aerogel was converted into aluminum/silicate aerogels after soaking in a solution of AlCl3. Then, the carbonization process takes place at a temperature of (150, 350, and 1100 °C) for 2 h to provide C/Al/Si aerogels with a density of around 0.18-0.040 gm/cm3 and porosity of 84-95%. The hybrid C/Al/Si aerogels presented interconnected networks of porous structures with different pore sizes depending on the carbon and PAAm contents. The sample with a solid content of 30% PAAm in the C/Al/Si aerogel was composed of interconnected fibrils whose diameter was about 50 µm. The structure after carbonization at 350 and 1100 °C was a condensed opening porous 3D network structure. This sample gives the optimum thermal resistance and a very low thermal conductivity of 0.073 (w/m·k) at low carbon content (2.71% at temperature 1100 °C) and high vpore (95%) compared with carbon content 42.38% and vpore (93%) which give 0.102 (w/m·k). This is because at 1100 °C, the carbon atoms evolve to leave an area between Al/Si aerogel particles, increasing the pore size. Furthermore, the Al/Si aerogel had excellent removal ability for various oil samples.

New 1,3,4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile.

A series of novel 1,3,4-thiadiazoles was synthesized via the reaction of N-(5-(2-cyanoacetamido)-1,3,4-thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer agents. The chemical structures of these derivatives were fully elucidated using various spectral and elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and therefore were excluded from further investigations. Derivatives 6b and 19 with IC50 at less than 10 µM and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1 percent of cells probably through induction of necrosis. These results were confirmed by the annexin V-PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19 significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket. Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate Lipinski's rule of five. In silico studies showed that these derivatives have a low blood-brain barrier penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve as potential anticancer agents and merit further investigations.

Association between polymorphisms and hypermethylation of CD36 gene in obese and obese diabetic Senegalese females.

BACKGROUND: Obesity and related metabolic disorders are associated with genetic and epigenetic alterations. In this study, we have examined the association between polymorphisms and hypermethylation of the CD36 gene promoter with obesity in Senegalese females with or without type 2 diabetes mellitus to identify novel molecular markers of these pathologies (obesity and type 2 diabetes mellitus). MATERIALS AND METHODS: The study was conducted in Senegal with healthy lean control, obese, and obese diabetic (age; 49.98 years ± 7.52 vs 50.50 years ± 8.76 vs 51.06 ± 5.78, and body mass index (BMI); 24.19 kg/m2 ± 2.74 vs 34.30 kg/m2 ± 4.41 vs 33.09 kg/m2 ± 4.30). We determined three genetic polymorphisms of CD36 i.e., rs1761667, rs1527483, and rs3211867 by real-time polymerase chain reaction, and methylation of CPG islands of CD36 was assessed by methylation-specific polymerase chain reaction (MS-PCR) in DNA isolated from peripheral blood of each participant. Plasma sCD36 levels and DNA methyltransferase 3a (DNMT3a) levels were determined by enzyme-linked immunosorbent assay (ELISA). According to the standard laboratory protocol, all biochemical parameters were analyzed from fasting serum or plasma. RESULTS: For rs1761667, obese and obese diabetic subjects had statistically significant different parameters depending on the genotypic distribution. These were waist size for obese and HDL cholesterol for obese diabetic, they were significantly higher in subjects harboring GG genotype of rs1761667 (respectively p = 0.04 and p = 0.04). For rs3211867, obese subjects harboring the AA/AC genotype had significantly higher BMI (p = 0.02) and total cholesterol (p = 0.03) than obese subjects harboring the CC genotype. At the same time, the obese diabetic subjects harboring the AA/AC genotype had total cholesterol levels significantly higher than the obese diabetic subjects harboring the CC genotype (p = 0.03). For rs1527483, only the control subjects had statistically significant different parameters depending on the genotypic distribution. The control subjects harboring the GG genotype had a significantly higher BMI than the control subjects harboring the AA/AG genotype (p = 0.003). The CD36 gene methylation was significantly 1.36 times more frequent in obese and obese diabetic compared to lean control (RR = 1.36; p = 0.04). DNMT3a levels were higher in subjects with CD36 gene methylation than in subjects without CD36 gene methylation in each group. Obese diabetic subjects with CD36 gene methylation had significantly fewer plasmas sCD36 (p = 0.03) and more LDL-cholesterol (p = 0.01) than obese diabetic subjects without CD36 gene methylation. In the control group, an increase in sCD36 levels would be associated with a decrease in total cholesterol and triglyceride levels (coef = -7647.56 p = 0.01 and coef = -2528.50 p = 0.048, respectively) would be associated with an increase in LDL cholesterol levels. For the obese group, an increase in sCD36 levels would be associated with an increase in fasting insulin levels (coef = 490.99 p = 0.02) and a decrease in glycated hemoglobin levels (coef = -1196.26 p = 0.03). An increase in the sCD36 levels would be associated with an increase in the triglyceride levels in the obese diabetic group (coef = 9937.41 p = 0.02). The AA/AC genotype of SNP rs3211867 polymorphism was significantly associated with CD36 gene methylation in the control and obese diabetic groups (respectively p = 0.05, p = 0.002; 95% CI). CONCLUSION: These observations suggest that polymorphisms and epigenetic changes in CD36 gene promoters may be implicated in the onset of obesity and its related complication type 2 diabetes mellitus.

Novel hit of DPP-4Is as promising antihyperglycemic agents with dual antioxidant/anti-inflammatory effects for type 2 diabetes with/without COVID-19.

DPP-4Is are well recognized therapy for type 2 diabetes. In spite of sharing a common mode of action, the chemical diversity among members of DPP-4Is raised the question whether structural differences may result in distinguished activities. DPP-4Is were recently explored as drug repurposing means for treatment of SARS-CoV-2 due to the urgent need for small molecule drugs for controlling infections. The use of DPP-4Is was not correlated with adverse COVID-19-related consequences among patients with type 2 diabetes. Inspired by these reasons and the importance of pyrimidinone ring as DPP-4I with both antioxidant and anti-inflammatory activities, we succeeded to prepare some novel pyrimidinone and thio-pyrimidinone derivatives, which were then screened for their antidiabetic activity and DPP-4 inhibition. In addition, their anti-inflammatory effect on LPS-stimulated RAW 264.7 cells were evaluated. Furthermore, their antioxidant activities were also tested.

Patterns and distribution of de novo mutations in multiplex Middle Eastern families.

While de novo mutations (DNMs) are key to genetic diversity, they are also responsible for a high number of rare disorders. To date, no study has systematically examined the rate and distribution of DNMs in multiplex families in highly consanguineous populations. Leveraging WGS profiles of 645 individuals in 146 families, we implemented a combinatorial approach using 3 complementary tools for DNM discovery in 353 unique trio combinations. We found a total of 27,168 DNMs (median: 70 single-nucleotide and 6 insertion-deletions per individual). Phasing revealed around 80% of DNMs were paternal in origin. Notably, using whole-genome methylation data of spermatogonial stem cells, these DNMs were significantly more likely to occur at highly methylated CpGs (OR: 2.03; p value = 6.62 × 10-11). We then examined the effects of consanguinity and ethnicity on DNMs, and found that consanguinity does not seem to correlate with DNM rate, and special attention has to be considered while measuring such a correlation. Additionally, we found that Middle-Eastern families with Arab ancestry had fewer DNMs than African families, although not significant (p value = 0.16). Finally, for families with diseased probands, we examined the difference in DNM counts and putative impact across affected and unaffected siblings, but did not find significant differences between disease groups, likely owing to the enrichment for recessive disorders in this part of the world, or the small sample size per clinical condition. This study serves as a reference for DNM discovery in multiplex families from the globally under-represented populations of the Middle-East.

Novel pyrrolopyrimidine derivatives: design, synthesis, molecular docking, molecular simulations and biological evaluations as antioxidant and anti-inflammatory agents.

Current medical approaches to control the Covid-19 pandemic are either to directly target the SARS-CoV-2 via innovate a defined drug and a safe vaccine or indirectly target the medical complications of the virus. One of the indirect strategies for fighting this virus has been mainly dependent on using anti-inflammatory drugs to control cytokines storm responsible for severe health complications. We revealed the discovery of novel fused pyrrolopyrimidine derivatives as promising antioxidant and anti-inflammatory agents. The newly synthesised compounds were evaluated for their in vitro anti-inflammatory activity using RAW264.7 cells after stimulation with lipopolysaccharides (LPS). The results revealed that 3a, 4b, and 8e were the most potent analogues. Molecular docking and simulations of these compounds against COX-2, TLR-2 and TLR-4 respectively was performed. The former results were in line with the biological data and proved that 3a, 4b and 8e have potential antioxidant and anti-inflammatory effects.

Synthesis of Some Novel Benzimidazole Derivatives as Anticancer Agent and Evaluation for CDK2 Inhibition Activity.

BACKGROUND: Thiobezimidazoles reveal various pharmacological activities due to similarities with many natural and synthetic molecules; they can easily interact with biomolecules of living systems. OBJECTIVE: A series of substituted 2-thiobezimidazoles have been synthesized. Twelve final compounds were screened for in vitro anti-cancer activities against sixty different cell lines. METHODS: The spectral data of the synthesized compounds were characterized. A docking study for active anticancer compounds and CDK2/CyclinA2 Kinase assay against standard reference; Imatinib, were performed. RESULTS: Two compounds (3c&3l) from the examined series revealed effective antitumor activity in vitro against two-cancer cell lines (Colon Cancer (HCT-116) and Renal Cancer (TK-10). The docking study of synthesized molecules discovered a requisite binding pose in the CDK-ATP binding pocket .3c &3l were promoted in the CDK2/CyclinA2 Kinase assay against standard reference Imatinib. CONCLUSION: Against all tested compounds; two compounds 3c &3l were found active against two types of cell-lines.

Synthesis, Antiproliferative Activity, and Apoptotic Profile of New Derivatives from the Meta Stable Benzoxazinone Scaffold.

BACKGROUND: Cancer exerts a huge strain on the health system. The emerging resistance to the current chemotherapies demands the continuous development of new anticancer agents with lower cost, higher efficacy, and greater specificity. OBJECTIVE: This study aimed at developing selective small molecules as targeted anticancer agents. METHODS: The behavior of benzoxazinone 2 towards nitrogen nucleophiles, such as hydrazine hydrate, formamide, ethanolamine, aromatic amines, and thiosemicarbazide, was described. The behavior of the amino quinazolinone 3 towards carbon electrophiles and P2S5 was also investigated. The antiproliferative activity of 17 new benzoxazinone derivatives was examined against the growth of three human cancer cell lines; liver HepG2, breast MCF-7, and colon HCT-29, in addition to the normal human fibroblasts WI-38, and the selectivity index was calculated. The possible molecular pathways, such as the cell cycle and apoptosis, were investigated. RESULTS: Derivatives 3, 7, 8, 10, 13, and 15 had a significant (less than 10 µM) antiproliferative activity against the three cancer cell lines investigated. Derivative 7 showed the best antiproliferative profile comparable to that of doxorubicin. The selectivity index for all the effective derivatives ranged from ~5-12 folds, indicating high selectivity against the cancer cells. Derivative 15 caused ~ 7-fold and 8-fold inductions in the expression of p53 and caspase3, respectively. It also caused a ~ 60% reduction in the expression of both topoisomerase II (topoII) and cyclin-dependent kinase 1 (cdk1). Derivatives 3, 7, and 8 had a similar profile; ~ 6-8-fold increased in the expression of p53 and caspase3 but these compounds were devoid of any significant effect on the expression of topoII and cdk1. Derivatives 10 and 13 were also similar and resulted in a ~6-fold elevation in the expression ofcaspase3, and more than 60% downregulation in the expression of topoII. The results of the gene expression of topoII and caspase3 were confirmed by the measurement of the topoII concentration and caspase3 activity in the HepG2 cells. CONCLUSION: Six derivatives exerted their antiproliferative activity by arresting the cell cycle (decreasing cdk1), preventing the DNA duplication (downregulating topo II), and inducing apoptosis (inducing p53 and caspase3). One common feature in all the six active derivatives is the presence of a free amino group. These compounds have merit for further investigations.

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking.

In an effort to discover potent anticancer agents, 2-thiouracil-5-sulfonamides derivatives were designed and synthesized. The cytotoxic activity of all synthesized compounds was investigated against four human cancer cell lines viz A-2780 (ovarian), HT-29 (colon), MCF-7 (breast), and HepG2 (liver). Compounds 6b,d-g, and 7b showed promising anticancer activity and significant inhibition of CDK2A. Moreover, they were all safe when tested on WI38 normal cells with high selectivity index for cancer cells. Flow cytometric analysis for the most active compound 6e displayed induction of cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells) and stimulated the apoptotic death of all cancer cells. Moreover, 6e was able to cause cycle arrest indirectly through enhanced expression of cell cycle inhibitors p21 and p27. Finally, molecular docking of compound 6e endorsed its proper binding to CDK2A, which clarifies its potent anticancer activity.

Synthesis of novel pyrroles and fused pyrroles as antifungal and antibacterial agents.

Pyrroles and its fused forms possess antimicrobial activities, they can easily interact with biomolecules of living systems. A series of substituted pyrroles, and its fused pyrimidines and triazines forms have been synthesised, all newly synthesised compound structures were confirmed by spectroscopic analysis. Generally, the compounds inhibited growth of some important human pathogens, the best effect was given by: 2a, 3c, 4d on Gram-positive bacteria and was higher on yeast (C. albicans), by 5c on Gram-negative bacteria and by 5a then 3c on filamentous fungi (A. fumigatus and F. oxysporum). Such results present good antibacterial and antifungal potential candidates to help overcome the global problem of antibiotic resistance and opportunistic infections outbreak. Compound 3c gave the best anti-phytopathogenic effect at a 50-fold lower concentration than Kocide 2000, introducing a safe commercial candidate for agricultural use. The effect of the compounds on DNA was monitored to detect the mode of action.

Antiproliferative Activity of Some Newly Synthesized Substituted Pyridine Candidates Using 4-(Aaryl)-6-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile as Synthon.

Herein, we used nicotinonitrile derivatives 4a,b as scaffolds to build novel and active antineoplastic agents. The reaction of nicotinonitrile derivatives 4a,b with POCl3/PCl5 and/or hydrazine hydrate afforded 2-chloropyridones 6a,b and 2-hydrazinyl nicotinonitrile derivatives 11a,b, respectively, as building blocks for various heterocyclic compounds. The structures of all of the synthesized heterocycles were elucidated from their spectral and elemental analyses. The cytotoxic activities of the prepared derivatives were evaluated against different cancer cell lines. Results revealed potential cytotoxic effects of the synthesized compounds against evaluated cell lines, where NCIH 460 and RKOP 27 cell lines were the most affected by the prepared compounds. Derivative 14a was the most effective against all tested cell lines in terms of the obtained IC50 values (25 ± 2.6, 16 ± 2, 127 ± 25, 422 ± 26, and 255 ± 2 nM against NCIH 460, RKOP 27, HeLa, U937, and SKMEL 28 cells, respectively).

Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5(4H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site.

In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment. Thus, new derivatives based on thiazol-5(4H)-ones have been designed and synthesized in an eco-friendly manner. The synthesized derivatives have the same essential pharmacophoric features of colchicine binding site inhibitors. The anti-proliferative activity of the new derivatives was evaluated on three human cancer cell lines (HCT-116, HepG-2, and MCF-7) using MTT assay procedure and colchicine was used as a positive control. Compounds 4f, 5a, 8f, 8g, and 8k showed superior antiproliferative activities against the three tested cell lines with IC50 values ranging from 2.89 to 9.29 µM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their anti-proliferative activity. Tubulin polymerization assay results were found to be comperable with the cytotoxicity results. Compounds 4f and 5a were the most potent tubulin polymerization inhibitors with an IC50 value of 9.33 and 9.52 nM, respectively. Further studies revealed the ability of 5a to induce apoptosis and arrest cell cycle growth at the G2/M phase. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the tubulin heterodimer active site. From these studies, it was concluded that inhibition of tubulin polymerization yields the reported cytotoxic activity.

Immunoglobulin G index as a biomarker of relapse response to corticosteroids during early stages of multiple sclerosis.

BACKGROUND: Despite the considerable advances in disease modifying therapy in multiple sclerosis (MS), management of acute MS relapses remains understudied. The response to relapse therapy is heterogenous among patients, and the exact reason behind such response remains elusive. Identification of a reliable biomarker for relapse responsiveness would contribute considerably to optimizing the relapse outcome. OBJECTIVES: to explore whether the immunoglobulin G (IgG) index during acute relapse contributes to relapse response to corticosteroid therapy or not. METHODS: A prospective study was conducted on 46 MS patients attending MS clinic in relapse with a baseline EDSS≤3 before the relapse. IgG index was measured in all patients before corticosteroids therapy, and their EDSS was re-assessed after 3 months. RESULTS: The mean age of the recruited patients was 26.89±4.19 years, with females constituting 71.7% of the sample. IgG index was significantly higher in patients who recovered fully after relapse (1.44) than those who were partially recovered (0.95)(P<0.001), and it was inversely correlated with EDSS increase after the relapse (r=-0.390, P = 0.007). On regression analysis, the OR of IgG index to relapse response was 0.05 (CI: 0.07-0.31, 95%)(P = 0.003). CONCLUSIONS: IgG index can be a promising biomarker of relapse response to steroids in early stages of MS.

Synthesis, Antiproliferative, and Antioxidant Evaluation of 2-Pentylquinazolin-4(3H)-one(thione) Derivatives with DFT Study.

The current study was chiefly designed to examine the antiproliferative and antioxidant activities of some novel quinazolinone(thione) derivatives 6-14. The present work focused on two main points; firstly, comparing between quinazolinone and quinazolinthione derivatives. Whereas, antiproliferative (against two cell lines namely, HepG2 and MCF-7) and antioxidant (by two methods; ABTS and DPPH) activities of the investigated compounds, the best quinazolinthione derivatives were 6 and 14, which exhibited excellent potencies comparable to quinazolinone derivatives 5 and 9, respectively. Secondly, we compared the activity of four series of Schiff bases which included the quinazolinone moiety (11a-d). In addition, the antiproliferative and antioxidant activities of the compounds with various aryl aldehyde hydrazone derivatives (11a-d) analogs were studied. The compounds exhibited potency that increased with increasing electron donating group in p-position (OH > OMe > Cl) due to extended conjugated systems. Noteworthy, most of antiproliferative and antioxidant activities results for the tested compounds are consistent with the DFT calculations.

Garlic and allopurinol attenuate hepatic apoptosis induced by fipronil in male albino rats.

Fipronil (FPN) can induce oxidative tissue damage and may be contemplated as an apoptosis inducer. Our aim is to investigate the possible hepatoprotective roles of garlic or allopurinol (ALP) against fipronil subacute toxicity. Thirty-six mature male albino rats were randomly divided into six groups; the first group was saved as control (C), the 2nd (G) was orally intubated with 500 mg/kg aqueous garlic extract, and the 3rd (A) received 150 mg/L allopurinol in their drinking water. The 4th group (F) was administered 13.277 mg/kg fipronil by gavage, while the 5th (G + F) and 6th (A + F) groups received the same doses of garlic and allopurinol, respectively two hours before fipronil intoxication. Our results revealed that FPN significantly increased the hepatic malondialdehyde, protein carbonyl levels, and the enzymatic activities of superoxide dismutase, catalase, glutathione peroxidase, and xanthine oxidase, but it decreased glutathione-S-transferase compared to the control group. Moreover, FPN exhibited significant up-regulation in the hepatic pro-apoptotic (Bax) and caspase-3 genes expression, down-regulation in the anti-apoptotic (Bcl-2) mRNA gene expression and induced DNA fragmentation. Surprisingly, garlic or allopurinol co-treatment ameliorated the hepatic lipid peroxidation, antioxidants disruption, and apoptosis induced by FPN. In conclusion, garlic and allopurinol relieved the oxidative injury and reduced the fipronil-induced apoptosis probably by improving the tissue antioxidant defense system.

Cytotoxic Effects of Newly Synthesized Heterocyclic Candidates Containing Nicotinonitrile and Pyrazole Moieties on Hepatocellular and Cervical Carcinomas.

In this study, a series of newly synthesized substituted pyridine 9, 11-18, naphthpyridine derivative 10 and substituted pyrazolopyridines 19-23 by using cycnopyridone 8 as a starting material. Some of the synthesized candidates are evaluated as anticancer agents against different cancer cell lines. In vitro cytotoxic activities against hepatocellular and cervical carcinoma cell lines were evaluated using standard MTT assay. Different synthesized compounds exhibited potential in vitro cytotoxic activities against both HepG2 and HeLa cell lines. Furthermore, compared to standard positive control drugs, compounds 13 and 19 showed the most potent cytotoxic effect with IC50 values of 8.78 ± 0.7, 5.16 ± 0.4 µg/mL, and 15.32 ± 1.2 and 4.26 ± 0.3 µg/mL for HepG2 and HeLa cells, respectively.

Evaluation of novel pyrrolopyrimidine derivatives as antiviral against gastroenteric viral infections.

Viral gastroenteritis is a major global public-health threat. All age groups are susceptible for this infection, but its most serious consequences affect children. Rotavirus, Coxsackievirus and Adenovirus are the most common viruses that cause gastroenteritis. Herein, we synthesized novel pyrrole, pyrrolo[2,3­d]pyrimidine and pyrrolo[3,2­e][1,2,4]triazolo[4,3­c]pyrimidine derivatives. The non-toxic doses of these compounds were determined using BGM cell lines. We examined all the new compounds for their anti-viral activities against Rotavirus Wa strain and Coxsackievirus B4. Compounds 2a, 2d, 5a, 5c, 5d, 7b, 7j, 7n, 14b, 14c, 14e and 14f exhibited significant antiviral activity. We interpreted the action of these compounds using molecular docking against the homology models of viral polymerase enzymes of these viruses. RMSD value of 5d/Coxsackievirus was higher than the RMSD value for 5d/rotavirus and hence better as a stability parameter, which can be correlated to the biological activity.