Synthesis of Mono- and Bis-Phosphonates via Transformations of PIII and PV Synthons as Bone Diseases Treatment Agents

Abstract

The thesis focuses on the phosphorus chemistry. The general part includes the most interesting reactions of alkyl phosphites, mainly, trialkyl and dialkyl phosphites, with C=X electrophiles (aldehydes, ketones, aldimines, ketimines, isocyanates, isothiocyanates, and activated olefins. The original work, contains four parts; all relied on applying a variety of phosphorus reagents on different substrates, that characterized by the presence of nitrogen containing heterocycles, such as pyridazine or triazole core structure for the purpose of pharmacological evaluation. According to the structures of the products and the data base (Molecular assisted molecular modeling), new synthesized phosphorus compounds were pharmacologically evaluated, e.g., as anti-nociceptive, anti-inflammatory, anti-microbial, antiarthritis or anticancer agents. The structure-activity relationship was studied in most cases. In the first part, a high-yielding general synthesis of imidazophosphor esters-based tetrazolo[1,5-b]pyridazine was described. A conjugated reaction between 3,6-diazidopyridazine and different types of phosphonyl carbanion reagents followed by intramolecular cyclization afforded the target products, using sodium ethanolate solution as the reaction medium. Among the products, 5 compounds, at 50 mg/kg dose showed notable anti-nociceptive and anti-inflammatory activity with low toxic-effect. In the second part, three different series of phosphonate derivatives, β-amino- and fused thiadiazolo/thiadiazine-phosphonates were synthesized using addition and/or addition-cyclization protocol of Horner-Wadsworth-Emmons (HWE) reagents to 1,2,4-triazole-3-thiols. The design of potentially antimicrobial and anticancer phosphor esters accounted to the results of the computer-assisted molecular modeling. All synthesized phosphonates are evaluated for their in vitro antimicrobial activities while anticancer properties were determined for eight out of twenty new phosphonates. The tested phosphonates, except compounds that have a nitrile moiety exhibit from moderate to significant antimicrobial activity. Nevertheless, the most active compounds are the fused thiadiazole-phosphonates that inhibited the growth of both Gram-negative and Gram-positive bacteria better than β-aminophosphonates and fused thiadiazolophosphonates. In parallel, the antitumor activity screenings of selected phosphonates representing each series are also tested. Their antitumor properties against ten carcinoma cell lines including breast, ovarian, prostate, and liver were investigated. The results showed that all tested compounds reflected remarkable antitumor activity against breast, and prostate carcinoma cell lines, whereas a moderate to good effect was observed on ovarian and liver carcinoma cell lines. In the third part, two different protocols for the synthesis of a variety of N-methylenebisphosphonates (N-MBPs) and their relevant bisphosphonic acids were reported, from (i) coupling of azido-substrates with the phosphorus reagent, tetraethyl methylene- bisphosphonate catalyzed by sodium ethanolate (EtONa); (ii) involved three-component one-pot synthesis, by applying tetraethyl methylene- bisphosphonate in an alkaline solution to carbodiimide- or Schiff-base derivatives, initially was generated in situ. The synthesized aminobis-phosphonates were pharmacologically evaluated for their antiarthritis/ anti-inflammatory activities. Furthermore, the structure-activity relationship were studied. The docking studies were also performed. In the fourth part, a new and an efficient conjugated addition reaction of phosphorus reagents (trialkyl- or dialkyl phosphites) with 2-azido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was developed and furnished spiro-triazaphosphole-oxides and phosphoramidate derivatives. Contrary to these results, linear substituted phosphoramidates were obtained from the reaction of the azide with dimethyl-, diethyl-, and diisopropyl phosphites. Reaction of hexaalkylphosphorus triamides with the same substrate afforded the corresponding phosphoric triamides in the presence of a protonating agent (dil alcohol). The new synthesized phosphorus compounds are reported and evaluated for anticancer activities. Keywords: Imidazophosphor; α-aminophosphonates; β-enaminobis-phosphonates; Horner-Wadsworth-Emmons reagents; spiro-triaza-phosphole-oxides; N-methylenebisphosphonates; anti-nociceptive; anti-inflammatory; anticancer; docking studies.