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. 2021 Oct 9;26(20):6099.
doi: 10.3390/molecules26206099.

T3P-Promoted Synthesis of a Series of 2-Aryl-3-phenyl-2,3-dihydro-4 H-pyrido[3,2- e][1,3]thiazin-4-ones and Their Activity against the Kinetoplastid Parasite Trypanosoma brucei

Lee J Silverberg  1 , Tapas K Mal  2 , Carlos N Pacheco  2   3 , Megan L Povelones  4 , Madeline F Malfara  4 , Anthony F Lagalante  5 , Mark A Olsen  5 , Hemant P Yennawar  6 , Hany F Sobhi  7 , Kayla R Baney  1 , Robin L Bozeman  1 , Craig S Eroh  1 , Michael J Fleming  1 , Tracy L Garcia  1 , Casey L Gregory  1 , Julia E Hahn  1 , Alyssa M Hatter  1 , Lexi L Johns  1 , Tianna L Klinger  1 , Jennie J Li  1 , Andrew J Menig  1 , Grace C Muench  1 , Melissa E Ramirez  1 , Jordyn Reilly  1 , Nicole Sacco  1 , Alexandra M Sheidy  1 , Marla M Stoner  1 , Eric N Thompson  1 , Soroush F Yazdani  1
Affiliations

T3P-Promoted Synthesis of a Series of 2-Aryl-3-phenyl-2,3-dihydro-4 H-pyrido[3,2- e][1,3]thiazin-4-ones and Their Activity against the Kinetoplastid Parasite Trypanosoma brucei

Lee J Silverberg et al. Molecules. .

Abstract

A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate-good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 µM concentration showed that five of the compounds strongly inhibited growth and killed parasites.

Keywords: N-aryl; T. brucei; T3P; imine; parasites; pyridothiazinone; thionicotinic acid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The 2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-one scaffold.
Scheme 1
Scheme 1
Preparation of 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones 1.
Scheme 2
Scheme 2
Tautomerization of 2-mercaptopyridine [20].
Scheme 3
Scheme 3
Tautomerization of aromatic 3 to nonaromatic 3T.
Figure 2
Figure 2
Drawing of the X-ray crystal structure of 3T. There is intramolecular O1-H---S1 hydrogen bonding and intermolecular N1-H---O2 hydrogen bonding.
Figure 3
Figure 3
Drawing of the X-ray crystal structure of the disulfide pyridine solvate from 3. Half of the molecular species in the crystal have the proton on the carboxylic acid oxygen (O1) and the other half have it on the pyridine (solvent) nitrogen (N2).
Scheme 4
Scheme 4
Possible reaction pathway.
Figure 4
Figure 4
Compounds 1a–1n were tested against long slender bloodstream form Trypanosoma brucei. Treated cells (50 µM) were compared to a vehicle control (DMSO) over the course of three days. The average of three replicates was plotted for treated cells with standard deviation shown as error bars. DMSO (vehicle) was plotted as the average of four replicates. Cell densities below the level of detection of the hemacytometer (104) are represented by 0, and are not shown on the graph. For example, 1f was not detectable at 18 h, 1d and 1g (overlapping on the graph) were not detectable at 42 h, and 1e was not detectable at 66 h. A table of the raw data is in the Supplementary Material.
See this image and copyright information in PMC

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