Ahmad F. Eweas

Design, synthesis, anti-schistosomal activity and molecular docking of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives.

Schistosomiasis remains one of the most prevalent parasitic infections and has significant public health consequences. Praziquantel (PZQ) is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Herein we report a series of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives, which were synthesized, characterized and tested as anti-schistosomal agents in vitro. Among all tested compounds, compounds 4a, 5b, and 7b at different tested concentrations (50, 100, and 200 μg/mL) showed the highest schistosomicidal activity. Among those 3 compounds, compound 7b was the most potent anti-schistosomal one. Moreover, all tested compound, at 50 μg/mL concentration, significantly reduced oviposition of adult worms in vitro. Furthermore, both compound 4a and 7b, as well as compound 6a, completely diminished egg deposition. To clarify the possible mechanism by which novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives act as anti-schistosomal agents, molecular docking of all new compounds was carried out using Molsoft ICM pro 3.5-0a to investigate the binding affinity and binding mode to thioredoxin glutathione reductase enzyme (TGR), a potential drug target for anti-schistosomal agents. The docking results revealed moderate to high affinity of the new compounds towards TGR. Compound 7b scored the highest binding energy (-101.13 kcal/mol) against TGR crystal structure forming eight hydrogen bonds with the amino acid residues at the binding site of the receptor. This result indicates that compound 7b could exert its effect through inhibition of TGR, which is a vital enzyme for schistosome survival.

Synthesis, anti-microbial evaluation, and molecular modeling of new pyrazolo[3,4-d]pyrimidine derivatives

Synthesis of some new pyrazolo[3,4-d]pyrimidine derivatives using readily available starting materials are described. A one-pot multi component cyclocondensation reaction was used to prepare the novel 3-methyl-4-aryl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-thiol which served as a new starting material for all new compounds in this research. The anti-microbial activities of the selective synthesized compounds have been evaluated. Some of the newly prepared compounds were found to have moderate to strong anti-microbial activity, e.g., compound 4a, 6a, and 8, in comparison to the reference drugs. Molecular modeling of the most three biologically active new compounds 4a, 6a, and 8 compared to the reference drugs tobramycin and fluconazole was carried out using Fieldalign 2.0 software.

Design, Synthesis, and Molecular Docking of Novel Pyrrolooxazepinediol Derivatives with Anti-Influenza Neuraminidase Activity.

A series of novel pyrrolo[2,1‐b][1,3]oxazepine‐8,9‐diol derivatives 12–15 were synthesized starting from l‐tartaric acid, which was transformed into anhydride which then reacted with allylamine in xylene to afford the imide 2. The target molecules 12–15 were achieved via ring‐closing metathesis with the Grubbs catalyst, followed by reduction of the carbonyl group and deprotection of hydroxyl groups. Finally, catalytic hydrogenation of the double bond afforded the title compounds 12–15. Molecular docking study of the title compounds 12–15 was carried out against neuraminidase as the target enzyme, in an attempt to understand the mechanism of action of the tested compounds as potential neuraminidase inhibitors. Molecular docking of the target compounds showed that all tested compounds bind to the active site of neuraminidase, with moderate to high binding energy. Compounds 12–15 were examined for their antiviral activity against H5N1 virus (A/chicken/Egypt/1/2008). Oseltamivir phosphate was used as a control for antiviral activity. The results show that compound 12 (EC50 = 0.016 μg/mL) exhibited potent anti‐influenza (H5N1) activity, which approximately equals that of oseltamivir (EC50 = 0.012 μg/mL). Also, it had a therapeutic index similar to that of oseltamivir phosphate (∼20). The data also revealed that compounds 13, 14, and 15 had slightly lower antiviral activity and lower cytotoxicity than oseltamivir phosphate, with LD50 of 0.188, 0.162, and 0.176 μg/mL, respectively. However, 13, 14, and 15 had lower therapeutic indices than 12. In conclusion, we were able to synthesize cheap and potent anti‐H5N1 compounds.

Design, synthesis, anti-inflammatory, analgesic screening, and molecular docking of some novel 2-pyridyl (3H)-quinazolin-4-one derivatives

A novel series of 6-bromo-2-(4-pyridyl)-quinazolin-4(3H)-ones were synthesized by reacting 5-bromo anthranilic acid with isonictinoly chloride in the presence of acetic anhydride, which were further reacted with p-amino acetophenone to obtain 3-(4-acetylphenyl)-6-bromo-2-(pyridin-4-yl)quinazolin-4(3H)-one (3). Compound 3 underwent further reactions with different aldehydes to afford chalcone derivatives 4–10, which in turn underwent various cyclization reactions to afford cyclized products 15–18. 2-aminothiazole derivatives 12 obtained by reaction of 3 with bromine then with thiourea. Compound 14 obtained by treatment of 11 with KSCN followed by cyclization. Some of the synthesized compounds 4, 5, 12, 14, 15 and 18 were screened for both analgesic and anti-inflammatory activities. All tested compounds showed good analgesic and anti-inflammatory activity in comparison to the reference standard indomethacin. Compounds 4 and 5 showed the highest anti-inflammatory activity, while compounds 14 and 15 showed the highest analgesic activity among all the tested compounds.

Design, Synthesis, In Vivo Anti-inflammatory, Analgesic Activities andMolecular Docking of Some Novel Pyrazolone Derivatives

A novel series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one derivatives were synthesized. The synthesis started with the important building block 3, which was prepared via coupling of from 2-(bis (methylthio) methylene) malononitrile 1 with 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2. The 5-aminopyrazole derivatives 4-8 were prepared from the cyclocondensationof 3 with the appropriate sulfonohydrazides and pyridine- 4-carbohydrazide respectively. Cyclocondensation of 1 or 9 with pyridine-4-carbohydrazide and 4-methylbenzene sulfonohydrazide corresponding pyrazole derivatives 10, 11, 12 and 13. Condensation 2 and 1-isothiocyanato-4- methylbenzene 14 yielded 15 which was refluxed with malonic acid to yielded1-(1,5-dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4-yl)-2-thioxo-3-(2methylphenyl) dihydropyrimidine-4,6(1H,5H)-dione (16). All tested compounds showed analgesic and anti-inflammatory activities in comparison to the reference standard drugs tramadol, acetyl salicylic acid and indomethacin. Maximum protection against the thermal stimulus was observed at 90 min following the administration of the compound (5) (105.8%), which was statistically significant comparable to the reference drug tramadol (148.7%). Compounds (5, 6, 11 and 13) revealed their maximal analgesic effect after 60 min (68.5%, 77.5%, 84.6% and 89.7%, respectively), then their effect started to decrease. In addition, derivatives 10, 12 and 16 showed anti-inflammatoryactivity after 4 hours, which was greater than that of the reference drug indomethacin and reached the maximum effect at the 2nd h. Additionally, a molecular docking study was performed against the COX enzyme using the Molsfot ICM 3.8 software.

Targeting thioredoxin glutathione reductase as a potential antischistosomal drug target

Schistosomiasis represents a world health major problem affecting more than 206 million people worldwide. Up to date, praziquantel (PZQ) is the sole chemotherapeutic agent used in clinics for the treatment of schistosomiasis. The resistance to PZQ chemotherapy that has been emerged against some schistosome phenotypes represents the most serious PZQ-related problem so far. Therefore, it is clear that there is a substantial need to develop novel and effective antischistosomal agents in order to ensure the effective drug control of schistosomiasis in the future. It is well-documented that the thiol redox homeostasis of schistosomes is entirely based on a single enzyme named thioredoxin-glutathione reductase (TGR). Thus, TGR is an essential protein for the survival of schistosomes which means that TGR is a valid and promising target for the recent antischistosomal drug-discovery approaches. This review aimed to shed light on potential lead compounds that may inhibit TGR activity and consequently could be tested as a potential antischistsomal drugs. In the current review we discussed multiple drug discovery approaches for new compounds targeting TGR and its implementation.