Adel M. Moussa

Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.

Mass spectrometric study of some pyrazoline derivatives

The structures of some new carboxamide, thiocarboxamide, nicotinoyl and isonicotinoyl pyrazoline derivatives have been related to their mass spectral data. The ions produced under electron impact showed both the characteristic pyrazoline ion and unusual azete fragmentation patterns. These results suggest that the mass spectra of these pyrazoline derivatives are both position and substituent dependent. Fragmentations of the ions are discussed in view of their metastable transitions.

Synthesis and spectral studies of some novel ethyl (substituted phenylthio) acetate and propionate derivatives

Abstract Ethyl (substituted phenylthio) acetate and propionate derivatives have been synthesised, their structures were proved by IR, NMR and mass spectra.

Mild dehydration using trichlorotrifluoroacetone

Abstract The reaction of 1,1,1-trichloro-3,3,3-trifluoroacetone with 1[ddot] and 2[ddot] alcohols form the corresponding hemiketals which spontaneously eliminate water in presence of a catalytic amount of p-toluenesulfonic acid to produce the olefins in high yield.

The reaction of aroylacetaldehydes with aroylhydrazines

A series of aroylacetaldehyde aroylhydrazones were prepared and characterized. Their uv and1H nmr spectra suggest the enol-imine structure rather than the keto-imine form. ThepKa values of these aroylhydrazones were measured and correlated with the Hammett substitution constants. It was observed that benzoylacetaldehyde substituted in thep-position could be cyclized to form the 5-hydroxy-2-pyrazolines by refluxing in acidified ethanol, while formyldeoxybenzoin only gives the corresponding pyrazole due to steric requirements of the two phenyl groups.ZusammenfassungEs wurde eine Reihe von Aroylacetaldehyd-aroylhydrazonen hergestellt und charakterisiert. Ihre UV- und1H-NMR-Spektren sprechen eher für eine Enol-imin-Struktur und nicht für die Keto-imin-Form. DiepKa-Werte für die Aroylhydrazone wurden bestimmt und über die Hammett-Beziehung korreliert. Es wurde festgestellt, daßp-substituierte Benzoyl-acetaldehyde durch Rückflußkochen in angesäuertem Ethanol zu 5-Hydroxy-2-pyrazolinen cyclisiert werden können, während Formyldeoxybenzoin wegen der sterischen Gegebenheiten der zwei Phenylgruppen lediglich die entsprechenden Pyrazole ergibt.

Discovery of a Series of Potent and Selective Nucleotide Prodrug Inhibitors of Respiratory Syncytial Virus (RSV) Replication

Abstract Background RSV can cause severe respiratory tract infections in infants and the elderly. Current experimental therapies include polymerase and fusion inhibitors, but their clinical use may be limited by toxicity or rapid emergence of viral resistance. Here we report new nucleotide prodrugs that are selective for and highly active against RSV replication in vitro. Methods Novel nucleotide prodrugs were synthesized and tested for their ability to inhibit RSV replication in 3-dimensional preparations of differentiated normal human bronchial epithelial (dNHBE) cells. Drug selectivity was assessed in the anti-RSV assays at concentrations up to 100 µg/mL, and in 14-day exposures with human bone marrow stem cells and 3-day exposures with human induced pluripotent (iPS) cardiomyocytes at concentrations up to 100 µM. The formation and half-lives (t½) of analog triphosphates (TPs) of selected prodrugs were measured in phytohaemagglutinin-stimulated human peripheral blood mononuclear cells (PBMCs) incubated with 100 µM prodrug. After 8 hours, medium was replaced with fresh medium without drug and cell extracts were prepared at various time points and analyzed for intracellular levels of TPs. After single oral dosing of Golden Syrian hamsters with selected prodrugs (~60 mg/kg), plasma pharmacokinetics and lung levels of TPs were determined at 4 and 24 hours or at 24 and 72 hours post dose. Results The most potent nucleotide prodrugs inhibited RSV replication by 90% at concentrations (EC90) as low as 0.021 µM. None of the prodrugs tested showed significant cytotoxicity with dNHBE cells, bone marrow stem cells or cardiomyocytes. The t½ of the TPs formed in human PBMCs ranged from 1.3 to >5 days. In hamsters, plasma parent drug levels were ≤1 ng/mL, yet significant levels of the corresponding TPs were detected in lung tissue. Furthermore, the highest TP concentrations (up to 1344 ng/g) were observed at the latest sampling time point (up to 72 hours). Conclusion The data indicate that these potent new nucleotide prodrugs are metabolized to TPs that prevent RSV replication likely by inhibition of the viral RNA polymerase. Additionally, the long t½ observed for many of the TPs suggest that it might be possible to cure RSV infections with a single dose. IND enabling studies are ongoing, targeting clinical evaluation in early 2018. Disclosures S. Good, Atea Pharmaceuticals, Inc.: Employee and Shareholder, Salary; A. Moussa, Atea Pharmaceuticals, Inc.: Employee and Shareholder, Salary; J. C. Meillon, Oxeltis: Employee and Shareholder, Salary; X. J. Zhou, Atea Pharmaceuticals, Inc.: Employee and Shareholder, Salary; K. Pietropaolo, Atea Pharmaceuticals, Inc.: Employee and Shareholder, Salary; J. P. Sommadossi, Atea Pharmaceuticals, Inc.: Board Member, Employee and Shareholder, Salary

Spectral characteristics of the reaction products of 5−phenyl−2,3,4−furantrione with o-diamines

Abstract The 1H and 13C NMR and mass spectra of 2-(2-amino-4,5-dimethylphenylcarbamoyl)-3-(hydroxyphenylmethyl)-6,7-dimethylqinoxaline (2), 3-(hydroxyphenylmethyl)-6,7-dimethylquinoxalin-2-carboxylic-γ-lactone (5), 3-(hydroxyphenylmethyl)-6,7-dimethylquinoxalin-2-carboxylic acid phenylhydrazide (6), 3-[2-hydroxy-2-phenyl-1-(phenylhydrazono)ethyl]-6,7-dimethyl-2(1H)-quinoxalinone (7), 2,3-dihydro-6,7-dimethyl-3-phenylhydrazono-2-phenylfuro[2,3-b]auinoxaline (8), 3-(hydroxyphenylmethyl)-6,7-dimethyl-1-phenylflavazole (9), and 3-(acetoxyphenylmethyl)-6,7-dimethyl-1-phenylflavazole (10) have been studied.