The acetylcholinesterase and carbonic anhydrase inhibitors (AChEIs and
h
CAIs) remain key therapeutic agents for many bioactivities such as anti-Alzheimer and antiobesity antiepileptic, anticancer, antiinfective, antiglaucoma, and diuretic effects. Here, it has been attempted to discover novel multi-target AChEIs and
h
CAIs that are highly potent, orally bioavailable, may be brain penetrant, and have higher effectiveness at lower doses than tacrine and acetazolamide. After detailed investigations both in vitro and in silico, novel
N
-substituted sulfonyl amide derivatives (
6a–j
) were determined to be highly potent inhibitors for AChE and
h
CAs (
K
I
s are in the range of 23.11–52.49 nM, 18.66–59.62 nM, and 9.33–120.80 nM for AChE,
h
CA I, and
h
CA II, respectively). Moreover, according to the cytotoxic effect studies, such as the ADME-Tox, cortex neuron cells, and neuroblastoma SH-SY5Y cell line, compounds
6a
,
6d
, and
6h
, which are the most potent representative versus the target enzymes, were identified as orally bioavailable, highly selective, and brain preferentially distributed AChEIs and
h
CAIs. The docking studies revealed precise binding modes between
6a
,
6d
, and
6h
and
h
CA II,
h
CA I, and AChE, respectively. The results presented here might provide a solid basis for further investigation into more potent AChEIs and
h
CAIs.
Graphical abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s11030-022-10422-8.
