Combinatorial Chemistry & High Throughput Screening - Volume 24, Issue 1, 2021

Background: Sulfur-(SM) and nitrogen (NM)-based mustards are the mutagenic incapacitating compounds which are widely used in vesicating the chemical warfare and cause toxicity in many organs, especially skin. SM, as a potent vesicating agent, contributes to the destruction of skin in dermis and epidermis layers. The progression of the lesion depends on the concentration of SM and the duration of exposure. Body responses start with pruritus, erythema, edema and xerosis, which lead to the accumulation of immune cells in the target sites and recruitment of mast cells and paracrine-mediated activity. Pro-inflammatory effectors are accumulated in the epidermis, hair follicles, and sebaceous glands resulting in the destruction of the basement membrane beneath the epidermis. There is still no satisfactory countermeasure against SM-induced lesions in clinical therapy, and the symptomatic or supportive treatments are routine management approaches. Objective: The current review highlights the recent progression of herbal medicines application in SM-induced injuries through the illustrative examples and also demonstrates their efficacies, properties and mechanism of actions as therapeutic agents. Conclusion: Phytochemicals and herbal extracts with anti-bacterial, anti-inflammatory and antioxidant properties have been recently shown to hold therapeutic promise against the SM-induced cutaneous complications. The present review discusses the possible application of herbal medicines in the healing of SM-induced injuries.

Background: Genus Erythrina belongs to family Fabaceae, which is widely distributed in tropical and subtropical areas. It has been used in both traditional herbal medicines and pharmacological applications. Original research articles and publications on the overview of alkaloids related to this genus are available, but a supportive systematic review account which highlighted phytochemical aspects of other types of secondary metabolites is currently insufficient. Objective: With the utilization of data and information from SCI-Finder, Google Scholar, the Web of Science, Scopus, Science Direct, PubMed, Chemical Abstracts, ACS journals, Springer, Taylor Francis, Bentham Science and IOP Science, the reliable material sources of this systematic review paper were obtained from the literature published from the 1980s to now. Conclusion: A vast amount of data showed that the non-alkaloidal secondary metabolites were obtained from genus Erythrina with various classes of chemical structures. Herein, approximately five hundred constituents were isolated, comprising flavonoids, terpenoids, saponins, phytosterols, phenols, arylbenzofurans, coumarins, alcohols, ceramides, mono-sugars and fatty acid derivatives. In agreement with the previous phytochemical reports on the plants of the family Fabaceae, flavonoids reached a high amount in the plants of genus Erythrina. Numerous biological activity investigations such as anti-bacteria, anti-cancer, anti-virus using isolated compounds from Erythrina species suggested that secondary metabolites of Erythrina plants are now becoming the promising agents for drug developments.

The emergence of drug-resistant strains among the variety of pathogens worsens the situation in today's scenario. In such a situation, a very heavy demand for developing the new antibiotics has arisen, but unfortunately, very limited success has been achieved in this arena till now. Infectious diseases usually make their impression in the form of severe pathology. Intracellular pathogens use the host's cell machinery for their survival. They alter the gene expression of several host's pathways and endorse to shut down the cell's innate defense pathway like apoptosis and autophagy. Intracellular pathogens are co-evolved with hosts and have a striking ability to manipulate the host's factors. They also mimic the host molecules and secrete them to prevent the host's proper immune response against them for their survival. Intracellular pathogens in chronic diseases create excessive inflammation. This excessive inflammation manifests in pathology. Host directed therapy could be alternative medicine in this situation; it targets the host factors, and abrogates the replication and persistence of pathogens inside the cell. It also provokes the anti-microbial immune response against the pathogen and reduces the exacerbation by enhancing the healing process to the site of pathology. HDT targets the host's factor involved in a certain pathway that ultimately targets the pathogen life cycle and helps in eradication of the pathogen. In such a scenario, HDT could also play a significant role in the treatment of drugsensitive as well with drug resistance strains because it targets the host's factors, which favors the pathogen survival inside the cell.

Aim and Objective: Oxidative stress is implicated in the development and progression of many diseases. Some of the appropriate actions that could taken to resolve the problem of these diseases are search for new antioxidant substances isolated from plants. The aims of this study were to research the intraspecies variations of A. verticillata and C. caeruleus essential oils from 8 locations using statistical analysis, the in vitro antioxidant properties of collective essential oils and in combinations. Materials and Methods: The essential oils were analyzed by GC and GC-MS. The intraspecies variations of the essential oil compositions were discussed using principal component analysis (PCA) and cluster analysis (CA). The antioxidant properties were evaluated DPPH-radical scavenging activity and β-carotene bleaching test. Results: The main components of Ammoides verticillata collective essential oil (Coll EO) were thymol (30.5%), carvacrol (23.2%), p-cymene (13.1%), limonene (12.5%) and terpinene-4-ol (12.3%). While roots of Carthamus caeruleus essential oil were dominated by carline oxide (86.2%). The chemical variability allowed the discrimination of two main Groups for both Coll EOs. A direct correlation between the altitudes, climate and the chemical compositions was evidenced. Ammoides verticulata and Carthamus caeruleus Coll Eos showed good antioxidant activity. In binary mixture, the interaction between both Coll Eos and between oils rich of thymol and/or carvacrol with carlina oxide produced the best synergistic effects compared to individual essential oils and the synthetic antioxidant (BHT). Conclusion: Ammoides verticillata and Carthamus caeruleus essential oil blends can be used as a natural food preservative and alternative to chemical antioxidants.

Aim and Objective: Cells and tissues of the body are prone to oxidative damage as a result of an increased level of reactive oxygen species and nitrogen radical beyond the detoxifying ability of the endogenous antioxidant system. This study aimed to evaluate the ameliorative effect of methanolic extracts of Nigella sativa (MENS) against cadmium-induced blood oxidative stress and testicular toxicity in albino rats. Materials and Methods: Twenty-five (25) male albino rats, weighing (200 ± 20g), were randomly grouped into five groups (A-E). Group B (Negative Control) received intraperitoneal administration of cadmium chloride (CdCl2, 5 mg/kg) only, group C received CdCl2 and low dose MENS (300 mg/kg, oral), group D received CdCl2 and high dose MENS (600 mg/kg, oral), group E (Positive control) received CdCl2 and Vitamin C (200 mg/kg, oral), for 14 days. No treatment was administered to group A (Normal control). The oxidative state of the blood was assessed by measuring the blood levels or activities of MDA, CAT, GSH and SOD; while testicular injury was assessed by measuring serum testosterone level using ELISA. The testes were harvested for histopathological examination. Results: The results showed that cadmium induced a marked elevation in the level of MDA, and a decrease in SOD, CAT and GSH levels or activities (p<0.05 or p<0.01); but no significant alteration in the serum testosterone level was found (p>0.05); Histopathological studies on the testes showed that cadmium significantly induced testicular injury, which was however ameliorated by the seed extract of N. sativa. Conclusion: We conclude that N. sativa seed extract is potentially testiculoprotective and attenuates oxidative stress against harmful chemical toxins such as cadmium.

Aims & Objective: In this work, the multicomponent reaction of aldehydes, benzoylisothiocyanate and alkyl bromides in the presence of ammonium acetate, sodium cyanide and a catalytic amount of KF/Clinoptilolite nanoparticles (KF/CP NPs) in the water at 100oC was investigated. Materials and Methods: In these reactions, thiazole derivatives were produced in good to excellent yields and short time. Also, the antioxidant activity was studied for some newly synthesized compounds using the DPPH radical trapping and reducing of ferric ion experiments and comparing results with the synthetic antioxidants (TBHQ and BHT). Results: As a result, the compounds 4b showed excellent DPPH radical trapping and reducing the strength of ferric ion. These compounds have biological potential because of the thiazole core. For this reason, the antimicrobial activity of some synthesized compounds was studied by employing the disk diffusion test on Gram-positive bacteria and Gram-negative bacteria. Conclusion: The results of the disk diffusion test showed that these compounds prevented bacterial growth.

Background: Immune-related genes possess promising prognostic potential in multiple cancer types. Here, we describe the development of an immune-related prognostic signature for predicting prostate cancer recurrence. Methods: Prostate cancer gene expression profiles for 477 prostate cases, as well as accompanying follow-up information were downloaded from The Cancer Genome Atlas (TCGA) and GEO. The samples were divided into 3 groups and immune gene sets significantly associated with prognosis were identified by evaluating the relationship between the expression of 1039 immune genes and prognosis in the training set. Relative expression levels of these genes were used to identify prognostic gene pairs. LASSO was used for feature selection and robust biomarkers selected. Finally, the identified immune prognostic markers were validated using dataset and GEO validation dataset and their performance compared with existing prognostic models. Results: In total, 87 immune genes, significantly associated with prognosis, were identified and 2447 immune gene pairs (IRGPs) established. Univariate survival analysis identified 641 prognosis-associated immune gene pairs. 8-IRGPs were obtained via LASSO feature selection and an 8-IRGPs signature established. The 8-IRGPs signature exhibited an independent prognosis value in prostate cancer of the training set, test set, and external validation set (p = <0.001). The 5- year survival AUC in both the training set and the validation set was >0.7. The 8-IRGPs outperformed clinical tumor classification features, including T, N, radiation therapy (RT) and targeted molecular therapy (TMT) (p <0.01). In addition, we compared the prognostic characteristics of 8-IRGPs with 3 reported prostate cancers and found that 8-IRGPs achieved a high C index (0.85) and had the highest predictive performance within 10 years of follow-up (HR: 10.5). Finally, we integrated T, N, RT, TMT, and 8-IRGPs and generated a novel alignment chart to aid the prediction of prostate cancer recurrence in individual patients (p <0.01). Conclusion: Here, we identified an 8-IRGP novel prognostic signature for the prediction of prostate cancer recurrence.

Background: Increasing the resistance issue has become the reason for the development of new antibacterial in crucial condition. Many ways are tracked to determine the most effective antibacterial agent. Some proteins that are a key role in bacteria metabolism are targeted, including MurA in cell wall biosynthesis and gelatinase biosynthesis-activating pheromone (GBAP) in Fsr Quorum Sensing (QS) system. Objective: The objective of this research is the analysis of compounds 1-4 from M. pendans as antibacterial and anti-QS activity trough protein inhibition by in silico study; focus on the structure-activity relationships, to appraise their role as an antibacterial and anti-QS agent in the molecular level. Methods: Both activities of M. pendans compounds (1-4) were analyzed by in silico, compared to Fosfomycin, Ambuic acid, Quercetin, and Taxifolin as a standard. Chemical structures of M. pendans compounds were converted using an online program molview. The compounds were docked to MurA, GBAP, gelatinase and serine protease using Autodock Vina in Pyrx 0.8 followed PYMOL to visualization and proteis.plus program to analyze of the complex. Results: All compounds from M. pendans bound on MurA, GBAP, gelatinase and serine protease except compound 2. This biflavonoid did not attach to MurA and serine protease yet is the favorable ligand for GBAP and gelatinase with the binding affinity of -6.9 and -9.4 Kcal/mol respectively. Meanwhile, for MurA and serine protease, compound 4 is the highest of bonding energy with values of -8.7 and -6.4 Kcal/mol before quercetin (MurA, -8.9 Kcal/mol) and taxifolin (serine protease, -6.6 Kcal/mol). Conclusion: Based on the data, biflavonoid acts better as anti-QS than an inhibitor of MurA enzyme while the others can be acted into both of them either the therapeutic agent of anti-QS or antibacterial agent of MurA inhibitor.

Aims & Objective: An efficient procedure for the synthesis of pyrido[2,1-a]isoquinoline derivatives in excellent yields was investigated using catalyst-free multicomponent reaction of phthaladehyde, methylamine, activated acetylenic compounds, alkyl bromides and triphenylphosphine in water under ultrasonic irradiation at room temperature. In addition, Diels- Alder reactions of pyrido[2,1-a]isoquinoline derivatives with activated acetylenic compounds under ultrasonic irradiation are investigated in two procedures. The advantages of this procedure compared to report methods are short time of reaction, high yields of product, easy separation of product, clean mixture of reaction and green media for performing reaction. In addition, because of having isoquinoline core in synthesized compounds, in this research antioxidant activity of some synthesized compounds was studied. Materials and Methods: To a stirred mixture of phthalaldehyde 1 (2 mmol) and methylamine 2 (2 mmol) in water (3 mL) under ultrasonic irradiation was added to activated acetylenic compounds 4 after 20 min. Alkyl bromide 3 and triphenylphosphine 5 react in another pot in water (3 mL) under ultrasonic irradiation for 15 min. After this time, this mixture was added to the first pot. After completion of the reaction, the solid residue was separated by filtration and washed with Et2O to afforded pure title compound 6. Results: In this work, generation of pyrido[2,1-a]isoquinoline derivatives 6 are performed using phthalaldehyde 1, methylamine 2, α-halo substituted carbonyls 3, activated acetylenic compounds 4 and triphenylphosphine 5 in water under ultrasonic irradiation condition at room temperature in excellent yield at short time. Conclusion: In summary, multicomponent reaction of phthaladehyde, methylamine, activated acetylenic compounds, alkyl bromides and triphenylphosphine in water under ultrasonic irradiation at room temperature produced pyrido[2,1-a]isoquinoline derivatives in excellent yields. Also, Diels-Alder reaction of pyrido[2,1-a]isoquinoline derivatives with activated acetylenic compounds and triphenylphosphine under ultrasonic irradiation is investigated in two procedures. Also, the antioxidant activities of 6a, 6c, 6g and 6i were evaluated by DPPH radical scavenging and ferric reducing power analyzes. The compounds 6a exhibit excellent DPPH radical scavenging activity and FRAP compared to synthetic antioxidants BHT and TBHQ. The chief benefits of our method are high atom economy, green reaction conditions, higher yield, shorter reaction times, and easy work-up, which agree with some principles of green chemistry.

Aim and Objective: Calculus Bovis (CB) has been employed to treat diseases for a long time. It has been identified to play significant anti-inflammatory and anti-tumor roles. However, the mechanism of treating primary liver cancer (PLC) remains to be revealed. This study aims to clarify the molecules and mechanisms of CB in treating PLC. Materials and Methods: After oral bioavailability (OB) and drug-likeness (DL) screening, 15 small molecules were identified as the potential ingredients against PLC. Following this, related targets network constructions and pathways were applied to clarify the mechanism of CB in treating PLC. An in vitro experiment was carried out to identify the function of CB in treating PLC. Results: Eleven compounds of CB were identified that play an anti-PLC role, including oleanolic acid, ergosterol, ursolic acid, etc. The potential targets which were observed include IL6, MAPK-8, VEGFA, Caspase-3, etc. Further analysis showed that the mechanism of CB in the treatment of PLC involved apoptosis-related pathways and immune-related pathways. Conclusion: In summary, the current study combines network pharmacology and in vitro experiments to reveal the mechanism of CB against PLC. We concluded that 11 ingredients of CB have an anti-PLC effect. Furthermore, CB plays a key role in treating PLC mainly by apoptosisrelated pathways and immune-related pathways. Our experiment verifies that CB promotes the apoptosis of SMMC-7721.

Aim and Objective: In the last decades, it has extensively been verified that nanostructured transition metal oxides emerge as inexpensive, available and extremely efficient heterogeneous catalysts in chemical transformations. The high electrical conductivity, high carrier concentration, and improved reactivity in cadmium oxide nanoparticles (CdO NPs) make it as a potential candidate for applications in the fields of nanocatalysis. [1]Benzopyran and pyridopyrimidine derivatives compose major classes of heterocyclic compounds, which have a wide spectrum of biological activities. Materials and Methods: In the present work, we report a facile and highly effective synthesis of 8- aryl-8H-[1,3]dioxolo[4,5-g][1]benzopyran-6-carboxylic acids and 1,3-dimethyl-2,4-dioxo-5- phenyl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-carboxylic acids via CdO NPs catalyzed cyclo condensation reaction of 4-substituted phenylmethylidenepyruvic acids with 3,4- methylenedioxyphenol or 6-amino-1,3-dimethyluracil, which was accomplished under ethanoldrop grinding at room temperature. The described catalyst was prepared successfully by a simple precipitation method and characterized by the Fourier transformed infrared absorption (FT-IR) spectroscopy, X-Ray diffraction (XRD) analytical technique, and scanning electron microscopy (SEM). Results: A number of [1,3]dioxolo[g][1]benzopyran-6-carboxylic acids and pyrido[d]pyrimidine- 7-carboxylic acids were effectively synthesized in high yields (96-98%) within short reaction times (10-15 min). All synthesized compounds were well-characterized by IR, 1H and 13C NMR spectroscopy, and also by elemental analyses. Conclusion: In summary, we have developed a very simple and impressive procedure for the synthesis of 8-aryl-8H-[1,3]dioxolo[4,5-g][1]benzopyran-6-carboxylic acids and 1,3-dimethyl- 2,4-dioxo-5-phenyl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-carboxylic acids as biologically interesting structures in the presence of CdO NPs as an efficient recyclable heterogeneous catalyst. The remarkable advantages for the offered protocol compared with traditional methods are short reaction time, good yields of the products, and the ease of operation with simple work-up procedure.

Aim: The present study explored the clinical significance of microRNA-22 (miR-22) expression in lung squamous cell carcinoma and to explore the targeting relationship with vascular endothelial growth factor receptor 3 (VEGFR3). Methods: A total of 49 patients with lung squamous cell carcinoma who underwent surgical treatment were selected. The expression of miR-22 was detected by fluorescence quantitative realtime PCR (qPCR), the expression of VEGFR3 was detected by Western blotting assays, and D240 labeled microlymphatic vessels density (MLVD) was detected by immunohistochemistry (IHC). Lung squamous cell carcinoma cell line SK-MES-1 was selected and the targeting relationship between miR-22 and VEGFR3 was analyzed by double luciferase reporter gene assay. Western blotting assays were used to detect the expression of vascular endothelial growth factor-D (VEGFD) and D240 in the blank control group, empty vector transfection group, miR-22 transfection group, miR-22 and VEGFR3 co-transfection group. Results: The expression range of miR-22 in lung squamous cell carcinoma was 0.8-3.5. The expression of miR-22 in lung squamous cell carcinoma was significantly different by tumor maximum diameter, lymph node metastasis, vascular invasion and TNM stage. The expression of miR-22 was linked to survival time. There was a negative correlation between miR-22 and VEGFR3, miR-22 and MLVD. Double luciferase reporter gene assays showed that miR-22 reduced the luciferase activity of pGL3-VEGFR3-WT transfected cells. Compared with the control group, the expression of VEGF-D and D2-40 in the miR-22 transfection group was significantly decreased. However, VEGF-D and D240 in the miR-22 and VEGFR3 co-transfection group reversed the changes. Conclusion: We assumed that the abnormal expression of miR-22 in lung squamous cell carcinoma may be involved in the development and progression of lung squamous cell carcinoma. MiR-22 negatively regulated the target gene VEGFR3 to mediate lymphangiogenesis. The expression of miR-22 may also be linked to the prognosis of the disease.

Aim and Objective: In this work, we tried to introduce a non-toxic and stable organic compound named succinimide as a green and efficient organo-catalyst for the promotion of the synthesis of arylidene malononitrile and tetrahydrobenzo[b]pyran derivatives. Using this method led to a clean procedure to achieve these types of bioactive compounds without a specific purification step. The rate and yield of the reactions were excellent, and also succinimide showed acceptable reusability as the catalyst. Materials and Methods: In a 25 mL round-bottom flask, [A: a mixture of aromatic aldehyde (1 mmol), malononitrile (1.1 mmol) and B: a mixture of aromatic aldehyde (1.0 mmol), malononitrile (1.1 mmol)] and succinimide (0.2 mmol) in H2O/ EtOH [5 mL (1:1)] was stirred at 80 °C for an appropriate time. After completion of the reaction, which was monitored by TLC [n-hexane-EtOAc (7:3)], the mixture was cooled to room temperature, and the solid product was filtered, washed several times with cold distilled water to obtain the corresponding pure product. Results: After the optimization of the conditions and amount of the catalyst, a series of aromatic aldehydes containing either-electron-donating or electron-withdrawing substituents were successfully used for both of the reactions. The reactions rates and yields under the selected conditions were excellent. The nature and electronic properties of the substituents had no obvious effect on the rate and yield of the reaction. Meanwhile, the catalyst showed acceptable reusability for these two reactions. Conclusion: In this work, we have introduced Succinimide as a green and safe organo-catalyst for the efficient synthesis arylidene malononitrile and tetrahydrobenzo[b]pyran derivatives. The results showed that the catalyst had excellent efficiency in green aqueous media and also the reusability of the catalyst was good.