Mohamed G. Badrey

Novel anti-HIV-1 NNRTIs based on a pyrazolo[4,3-d]isoxazole backbone scaffold: design, synthesis and insights into the molecular basis of action

A series of novel pyrazolo[4,3-d]isoxazoles was synthesized employing the thioamide synthon 3 to obtain the phenyldiazenylthiazolyl derivatives 7a–f, the thiazolyl derivative 9, the carbohydrazonamide 12 and the triazinyl counterparts 14a–c. The prepared compounds were screened for their antiviral activities against two viral strains of HIV-1 (RF and IIIB). All the compounds exhibited a highly potent antiviral capacity, having submicromolar to subnanomolar EC50 values with all derivatives being more active against the tested HIV strains than the reference drug efavirenz. The therapeutic index of these novel pyrazoloisoxazoles was also evaluated against the host cells CEM-SS or MT-4 and they exhibited a high therapeutic window. To further investigate the molecular basis of their actions, the inhibitory ability of these compounds was bioscreened against the HIV-1 viral enzyme reverse transcriptase (RT). The observed very potent inhibitory power of the pyrazolo[4,3-d]isoxazoles against RT prompted a molecular docking study to try exploring the potential binding modes of these compounds with their respective molecular targets. Finally, in vitro exploration of the metabolic stability of this series of compounds was evaluated by employing a rat-plasma half-life assay and they demonstrated reasonable hydrolytic resistance.

3-Amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H- chromeno (2,3-d )pyrimidine: An Effecient Key Precursor for Novel Synthesis of Some Interesting Triazines and Triazepines as Potential Anti-Tumor Agents

A number of interesting heterocycles were prepared through interaction of the intermediate 3-amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H-chromeno-[2,3-d]pyrimidine (1) and reagents such as hydrazonyl halides 2 to furnish triazine derivatives 4a–l. Reaction of 1 with phenacyl bromide afforded compound 5. Moreover, the title compound 1 was subjected to condensation with active methylene compounds (ethyl acetoacetate and ethyl benzoylacetate) to give triazipinones 8a,b. The condensation with aromatic aldehydes afforded either the triazole derivatives 10a–d or Schiff base 11. In addition, the behaviour of compound 1 towards activated unsaturated compounds namely dimethyl acetylene dicarboxylate and ethoxymethylenemalonitrile was studied and it was found to furnish the triazine 13 and triazepine derivative 15, respectively. Combination of title compound 1 with chlorinated active methylene compounds delivered the triazine derivatives 18a–c. Reaction of 1 with chloroacetonitrile furnished compound 20. The structures of the products were elucidated based on their microanalyses and spectroscopic data. Finally, the antitumor activity of the new compounds 4a and 8a against human breast cell MCF-7 line and liver carcinoma cell line HepG2 were recorded.

Heterocyclisation of 2,5-diacetyl-3,4-disubstituted-thieno[2,3- b ]thiophene bis-thiosemicarbazones leading to bis-thiazoles and bis-1,3,4-thiadiazoles as anti-breast cancer agents

In this paper, the synthesis of bis-thiazoles and bis-1,3,4-thiadiazoles linked to a thienothiophene nucleus is described. The synthesis was achieved through interaction between 2,5-diacetylthieno[2,3-b]thiophene bis-thiosemicarbazones with a variety of hydrazonyl halides in a basic medium. All the synthesised compounds were characterised by IR, 1H NMR, 13C NMR and mass spectroscopic analyses. The newly synthesised compounds represent a variety of novel polyheteroatomic moieties containing nitrogen and sulfur. Most of the synthesised compounds were evaluated for their antitumour activity against the breast cancer MCF-7 cell line. The results revealed that four compounds are equipotent to tamoxifen (IC50 = 8.04 μg mL−1) with IC50 = 8.23, 8.26, 8.68 and 9.12 μg mL−1 respectively.

Novel 4-heteroaryl-antipyrines as DPP-IV inhibitors.

Type 2 diabetes mellitus is a vast growing progressive disease that almost affects one person among every twelve globally. Regardless the availability of wide variety of oral hypoglycemics, only one‐third of patients achieves proper glycemic control. With the advantage of the low risk of hypoglycemia, DPP‐IV attracted the attention of medicinal chemists as a new target for oral hypoglycemics. In this report, a lead compound 1, with antipyrine scaffold, was obtained, and its binding mode was calculated. Several derivatives with bridged nitrogenous heterocycles have been synthesized via multicomponent reaction under controlled microwave heating conditions. The antidiabetic activity versus DPP‐IV protein was evaluated and compared with sitagliptin. Compounds with smaller‐ or medium‐sized nitrogenous bridges were comparable with sitagliptin in terms of DPP‐IV inhibitory activity, potentially via targeting Glu203 and Glu204. The oral hypoglycemic activities of compounds with submicromolar IC50 values were further evaluated using diabetic mouse model.

A convenient synthesis of some new thiazole and pyrimidine derivatives incorporating a naphthalene moiety

The reaction of 2-[1-(naphthalen-2-yl)ethylidene]hydrazinecarbothioamide with hydrazonoyl halides afforded new thiazole derivatives, whilst reaction with compounds containing an activated double bond such as ethoxymethylene-malononitrile and benzylidenemalononitrile yielded the respective pyrimidine derivatives. A 4-thiazolidin-4-one was obtained by reaction of the hydrazinecarbothioamide with ethyl bromoacetate. Subsequent condensation of the thia-zolidinone with aromatic aldehydes afforded the corresponding arylidene derivatives. Treatment of the hydrazinecarbothioamide with dimethyl acetylenedicarboxylate resulted in the formation of a (methoxycarbonylmethylidene) thiazolinone. Reaction of the hydrazinecarbothioamide with 2-chloro-1,3-dicarbonyl compounds gave the respective thiazole derivatives. The structures of the newly synthesised compounds were confirmed by their elemental analysis and spectral data.

Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors

The usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by their gastrointestinal side effects. Non-selective cyclooxygenases inhibitors interfere with both COX-1 and COX-2 isozymes. Since COX-1 mediates cytoprotection of gastric mucosa, its inhibition leads to the undesirable side effects. On the other hand, COX-2 is undetectable in normal tissues and selectively induced by inflammatory stimuli. Therefore, it is strongly believed that the therapeutic benefits derive from inhibition of COX-2 only. The presence of a strong connection between reported COX-2 inhibitors and cardiac toxicity encourages medicinal chemists to explore new scaffolds. In the present study, we introduced imidazopyrazolopyridines as new potent and selective COX-2 inhibitors that lack the standard pharmacophoric binding features to hERG. Starting from our lead compound 5a, structure-based drug-design was conducted and more potent analogues were obtained with high COX-2 selectivity and almost full edema protection, in carrageenan-induced edema assay, in case of compound 5e. Increased bulkiness around imidazopyrazolopyridines by adding a substituted phenyl ring(s) afforded less active compounds.