Table 3.

Optimization of 5-styryl-oxathiazolone inhibitors with regard to solubility.

Entry	Structure	Cmpd	Method, Yield	Mtb proteasome IC50 [nM]	Human proteasome IC50 [nM]	Solubility [μM]	Stability [%][a]
1		49	D; B, 7 %[b]	2750	77 000	84.7	91.6
2		50	D; A, 39 %[b]	15 000	29 500	2.1	97.7
3		51	C, 46 %; B, 45 %	2100	18 500	22.6	97.6
4		52	C, 75 %; B, 53 %	1150	11 300	19.7	99.1
5		53	C; B, 5 %[b]	735	3300	56.1	88.9
6		54	E; A, 3 %[b]	2350	>10 000[c]	64.6	n.d.
7		55	E; A, 15 %[b]	1350	>10 000[c]	70.6	n.d.
8		56	E; B, 4 %[b]	2100	>10 000[c]	2.4	n.d.
9		57	–, 31 %;[d] B, 12 %	1200	5000	4.1	n.d.

General method for the synthesis of 2-substituted acrylamides. Method C reagents and conditions: starting aryl iodide (1.0 equiv), acrylamide (2.0 equiv), Pd(OAc)₂ (0.05 equiv), tri-tert-butylphosphonium tetrafluoroborate (0.10 equiv), Et₃N (3.0 equiv), CH₃CN (4.0 mL mmol⁻¹), 120 °C MW, 15 min. Method D reagents and conditions:. starting aryl iodide (1.0 equiv), acrylamide (2.0 equiv) and Pd(OAc)₂ (0.05 equiv), Et₃N (3.0 equiv), CH₃CN (4.0 mL mmol⁻¹), 120 °C MW, 15 min. Method E reagents and conditions: starting aryl bromide (1.0 equiv), acrylamide (1.5 equiv) and trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (0.05 equiv), NaOAc (3.0 equiv), DMF (4.0 mL mmol⁻¹), 140 °C MW, 15 min.   [a] Chemical stability in PBS pH 7.4 at 25 °C; as % remaining after 24 h. [b] Isolated yield over two steps. [c] The compound interferes with the assay at 10 μm, therefore it was not possible to measure human proteasome inhibition. [d] Reagents and conditions: 1) (2E)-3-(1H-Indolyl-3-yl)acrylic acid (2.0 mmol), 1,1′-carbonyldiimidazole (2.0 mmol), DMF (10 mL), rt, 30 min, 2) NH₄HCO₃ (4.0 mmol), rt, o/n.