Discovery of phenylsulfonylfuroxan derivatives as gamma globin inducers by histone acetylation

Abstract

N-oxide derivatives 5(a-b), 8(a-b), and 11(a-c) were designed, synthesized and evaluated in vitro and in vivo as potential drugs that are able to ameliorate sickle cell disease (SCD) symptoms. All of the compounds demonstrated the capacity to releasing nitric oxide at different levels ranging from 0.8 to 30.1%, in vivo analgesic activity and ability to reduce TNF-α levels in the supernatants of monocyte cultures. The most active compound (8b) protected 50.1% against acetic acid-induced abdominal constrictions, while dipyrone, which was used as a control only protected 35%. Compounds 8a and 8b inhibited ADP-induced platelet aggregation by 84% and 76.1%, respectively. Both compounds increased γ-globin in K562 cells at 100 μM. The mechanisms involved in the γ-globin increase are related to the acetylation of histones H3 and H4 that is induced by these compounds. In vitro, the most promising compound (8b) was not cytotoxic, mutagenic and genotoxic.

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

“…Chelucci et al (2019) promising SCD treatment (Lanaro et al, 2018). Melo et al (2018) reported seven new phthalimide-furoxan conjugates (157-163) (Figure 13), and all the compounds were assessed for their antiplatelet properties. The research evaluated the prevalence of ADP and NO in platelet-based plasma using in vitro techniques.…”

“…Later in 2021, the same group reported new analogs (164-169) (Figure 13) for the treatment of SCD (Melo et al, 2018) values ranging from 0.3% to 6.3%. Treatment of CD34+ cells with compound 168 (at 2.5 µM), hydroxyurea (at 10 µM), and pomalidomide (at 1 µM) for 14 days showed significant induction of HbF by 168 compared to dimethyl sulfoxide induction (control).…”

Benzofuroxan Derivatives as Potent Agents against Multidrug‐Resistant Mycobacterium tuberculosis

“…This finding was consistent with the previous works published by our research group. [31][32][33] Therefore, the substitution of the N-acylhydrazone subunit was performed to overcome this inherent chemical instability. Similar to the Nacylhydrazone subunit-containing drug, the amide-containing drugs are also susceptible to hydrolysis, although at a much slower rate.…”

Design, synthesis and biological evaluation of N-oxide derivatives with potent in vivo antileishmanial activity

“…All data were expressed within ± 0.4% of the theoretical values. Compounds 3, 9, 12, 14b, and 14e were prepared according to previously described methodologies [23][24][25][26][27]. Compounds 4p-x were synthesized according to previously described methods and the characterization data are not shown here [24].…”

“…Then, compound (2) was treated with 4-hydroxybenzaldehyde and 1,8-diazabicyclo [5.4.0] undec7-ene (DBU) in a dichloromethane medium to provide compound (3) at a yield of 90% [21]. The amide-furoxan derivative ( 9) and benzofuroxan derivative (12) were obtained according to the previously described procedures [24,25]. Finally, the last step involved the coupling reaction of the aldehyde group in phenyl-furoxan (2), amide-furoxan ( 9), or benzofuroxan (12) within the appropriate hydrazides (5a-e; 6a-b) in medium containing ethanol and acetic acid at yields ranging from 82 to 96%, providing the Noxide compounds (4a-x) (Schemes 1 and 2).…”