Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment

Novel Benzothiazole-Based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer’s Disease Treatment

“…Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position. Replacement of the phenolic hydroxyl with an amine or methylhydroxy group led to loss of activity, which further confirms the importance of the 4-positioned phenolic hydroxyl as was previously suggested [9].…”

“…In this series, compounds 5 and 6 showed a huge improvement in potency with remaining 17β-HSD10 activity of 13.45% and 6.72%, respectively, at 25 μM. A significant finding from our previous work indicated that a p -hydroxy along m -chlorine substitution pattern displayed the most pronounced inhibitory activity [9], and a deviation from the 3-halogen and 4-hydroxyl pattern resulted in a dramatic decrease in 17β-HSD10 inhibition. Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position.…”

Novel Benzothiazole-Based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer’s Disease Treatment

“…Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position. Replacement of the phenolic hydroxyl with an amine or methylhydroxy group led to loss of activity, which further confirms the importance of the 4-positioned phenolic hydroxyl as was previously suggested [9].…”

“…In this series, compounds 5 and 6 showed a huge improvement in potency with remaining 17β-HSD10 activity of 13.45% and 6.72%, respectively, at 25 μM. A significant finding from our previous work indicated that a p -hydroxy along m -chlorine substitution pattern displayed the most pronounced inhibitory activity [9], and a deviation from the 3-halogen and 4-hydroxyl pattern resulted in a dramatic decrease in 17β-HSD10 inhibition. Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position.…”

Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer’s Disease Treatment

“…The 13 most potent compounds (residual activity < 55%) showed similar or even stronger inhibitory effects on 17β-HSD10 compared to the previously published compounds 13 and 14 ( Figure 1) [22]. All these compounds were used for the determination of IC 50 values, which ranged from~1 to 7 µM ( Table 1).…”

1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

“…Most interestingly, compounds K690 and K691 showed good inhibitory activity towards both CK1δ (IC 50 = 0.84 µM and 0.73 µM) and ABAD (39.8% and 38.6% inhibition at 10 µM 7 ; IC 50 = 1.89 µM and 1.67 µM) and such dual-activity could be of advantage for targeting AD. It is assumed that complex disorders, such as AD, could be more effectively targeted by multipotent compounds (also called multi-target directed ligands – MTDLs) able to intervene simultaneously in the different pathological events underlying the etiology of AD 10 , 13 .…”

Novel Benzothiazole-Based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer’s Disease Treatment

“…Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position. Replacement of the phenolic hydroxyl with an amine or methylhydroxy group led to loss of activity, which further confirms the importance of the 4-positioned phenolic hydroxyl as was previously suggested [9].…”

“…In this series, compounds 5 and 6 showed a huge improvement in potency with remaining 17β-HSD10 activity of 13.45% and 6.72%, respectively, at 25 μM. A significant finding from our previous work indicated that a p -hydroxy along m -chlorine substitution pattern displayed the most pronounced inhibitory activity [9], and a deviation from the 3-halogen and 4-hydroxyl pattern resulted in a dramatic decrease in 17β-HSD10 inhibition. Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position.…”

Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer’s Disease Treatment

“…The 13 most potent compounds (residual activity < 55%) showed similar or even stronger inhibitory effects on 17β-HSD10 compared to the previously published compounds 13 and 14 ( Figure 1) [22]. All these compounds were used for the determination of IC 50 values, which ranged from~1 to 7 µM ( Table 1).…”

1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

“…Most interestingly, compounds K690 and K691 showed good inhibitory activity towards both CK1δ (IC 50 = 0.84 µM and 0.73 µM) and ABAD (39.8% and 38.6% inhibition at 10 µM 7 ; IC 50 = 1.89 µM and 1.67 µM) and such dual-activity could be of advantage for targeting AD. It is assumed that complex disorders, such as AD, could be more effectively targeted by multipotent compounds (also called multi-target directed ligands – MTDLs) able to intervene simultaneously in the different pathological events underlying the etiology of AD 10 , 13 .…”

Novel Benzothiazole-Based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer’s Disease Treatment

“…Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position. Replacement of the phenolic hydroxyl with an amine or methylhydroxy group led to loss of activity, which further confirms the importance of the 4-positioned phenolic hydroxyl as was previously suggested [9].…”

“…In this series, compounds 5 and 6 showed a huge improvement in potency with remaining 17β-HSD10 activity of 13.45% and 6.72%, respectively, at 25 μM. A significant finding from our previous work indicated that a p -hydroxy along m -chlorine substitution pattern displayed the most pronounced inhibitory activity [9], and a deviation from the 3-halogen and 4-hydroxyl pattern resulted in a dramatic decrease in 17β-HSD10 inhibition. Our findings in this series further support this, and establish that the bulkier, 3-bromo and 3-iodo substitutions are even more favourable at this position.…”

Benzothiazolyl Ureas are Low Micromolar and Uncompetitive Inhibitors of 17β-HSD10 with Implications to Alzheimer’s Disease Treatment

“…The 13 most potent compounds (residual activity < 55%) showed similar or even stronger inhibitory effects on 17β-HSD10 compared to the previously published compounds 13 and 14 ( Figure 1) [22]. All these compounds were used for the determination of IC 50 values, which ranged from~1 to 7 µM ( Table 1).…”

1-(Benzo[d]thiazol-2-yl)-3-phenylureas as dual inhibitors of casein kinase 1 and ABAD enzymes for treatment of neurodegenerative disorders

“…Most interestingly, compounds K690 and K691 showed good inhibitory activity towards both CK1δ (IC 50 = 0.84 µM and 0.73 µM) and ABAD (39.8% and 38.6% inhibition at 10 µM 7 ; IC 50 = 1.89 µM and 1.67 µM) and such dual-activity could be of advantage for targeting AD. It is assumed that complex disorders, such as AD, could be more effectively targeted by multipotent compounds (also called multi-target directed ligands – MTDLs) able to intervene simultaneously in the different pathological events underlying the etiology of AD 10 , 13 .…”