New and efficient conjugate addition reaction of trimethyl, triethyl, and triisopropyl phosphites with 2-azido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was developed and furnished spiro-triazaphosphole-oxide derivatives in &70 % yield. Contrary to these results, linear substituted phosphoramidates were obtained from the reaction of the azide with dimethyl, diethyl, and diisopropyl phosphites.N-Alkylaminoor 2-aminotetrahydrobenzo[b]thiophene-3-carbonitrile was also isolated in *10 % yield from the previous two reactions. In the context of this work, hexaalkylphosphorus triamides were caused to react with the same substrate afforded the corresponding phosphoric triamides only in the presence of a protonating agent (dil. alcohol). The three reactions proceeded smoothly, cleanly, and were completed within *6 h at r.t. Pharmacological evaluation results of antibreast, anticolon, and antiprostate carcinoma cell lines properties for the products were discussed in terms of structure-activity relationship to define a chromophore for lead compounds. Graphical abstract

Design, synthesis and pharmacological screening of b-amino-, thiadiazole/thiadiazine-phosphonate based triazole motifs as antimicrobial/cytotoxic agents Three different series of phosphonate derivatives, b-aminoand fused thiadiazolo/thiadiazine-phosphonates have been synthesized using the 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 relied on the results of computer-assisted molecular modeling. All synthesized phosphonates were evaluated for their in vitro antimicrobial activities while anticancer properties were determined for eight out of twenty new phosphonates. The tested phosphonates, except for compounds that have a nitrile moiety, exhibited moderate to significant antimicrobial activity. Nevertheless, the most active compounds were fused thiadiazole-phosphonates, which inhibited the growth of both Gram-negative and Gram-positive bacteria better than b-aminophosphonates and fused thiadiazolophosphonates. In parallel, the antitumor activity screenings of selected phosphonates from each series and substra te 1 were also done. Their antitumor properties against ten carcinoma cell lines, including breast (MCF7, MDA-MB-231/ ATCC, MDA-MB-435, BT-549), ovarian (IGROVI, OVCAR-3, SK-OV-3), prostate (PX-3, PU-145), and liver (HEPG2), were investigated. The results showed that all synthesized compounds reflected remarkable antitumor activity against breast (especially MDA-MB-231/ATCC and BT-549), and pro state carcinoma cell lines (PC-3 and DU-145), whereas a moderate to good effect on ovarian and liver cancer cells was observed.

Dedicated to Professor Richard Neidlein on the occasion of his 77 th birthday N-Phthaloyl-alanylazide reacts smoothly with trialkyl phosphites producing the corresponding α-aminophosphates. With dialkyl hydrogenphosphonates in the presence of benzoyl peroxide, amidophosphates were the isolated products whereas the oxoaziridin-1-yl-phosphonic diamide was preferentially provided from the reaction of the azide with tris(dimethylamino)phosphine. The azide was also allowed to react with α-keto-, α-ethoxycarbonyl-and α-cyanomethylenetriphenylphosphorane to give the corresponding linear disubstituted 1,2,3-triazoles. Screening results of antibiotic potency for the products were discussed in terms of structure-activity relationship (SAR), and an attempt was made to define the structural features for lead compounds.

A series of 1,2,3‐triazol‐1‐ylbenzenesulfonamide derivatives was designed, synthesized and their ability to inhibit several carbonic anhydrase isoforms was evaluated. The basis of our design is to hybridize the benzenesulfonamide moiety widely used as a zinc‐binding group, a triazole ring as spacer with a tail of different substituted aryl moieties. The synthesis of these compounds was achieved using Cu(I)‐mediated click chemistry between the azide containing the benzenesulfonamide pharmacophore and various aryl acetylenes or 1,6‐heptadiyne through copper‐catalyzed [3+2] cycloaddition reaction. The ability the new derivatives to inhibit four human carbonic anhydrase isoforms hCA I, II, IX, and XII was evaluated. All the compounds exhibited good potency and high selectivity towards isoforms hCA I and II more than isoforms hCA IX and XII, especially for the derivatives 3c and 3j that displayed Ki of 2.8 and 3.8 nM against hCA II and a high hCA II selectivity ratio ranging from 77.6 to 3571.4 over other isoforms. All the compounds were docked in the active site of the downloaded hCA II active site and their binding pattern confirmed their significant activity by interacting of the sulfonamide moiety with zinc ion in the active site, in addition to its hydrogen bond interaction with Thr199 and Thr200. All the above‐mentioned findings pointed out towards the promising activity of the synthesized series that can be presented as a new scaffold to be further optimized as selective antiglaucoma drugs.

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