inhibitor E3 with an IC50 value of 7.68 μM. Other modification
did not bring about improved hMAO-B inhibitors either. This has
puzzled us. According to classic concept of the hydrophobic
effect, nonpolar solute molecules or moieties aggregate to
maximize the entropy. Nevertheless, the story described in this
manuscript does not follow this rule, which may challenge our
understanding of molecular interactions and molecular
recognition in biological systems. We hope the scientific
community will solve this paradox in the future after this article
is published.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21672050, 81803352 and 21572003) and
the Fundamental Research Funds for the Central Universities
(JZ2018HGBZ0167 and JZ2018HGTA0225).
Appendix A. Supplementary data
Scheme 4. Synthesis of Target Compounds E1 – E22. Regents and
conditions: (I) (1) (Boc)2O, Et3N, DMAP, CH2Cl2, rt, 2 h; (2) CF3COOH,
CH2Cl2, rt, 2 h; (II) methyl p-Toluenesulfonate (methyl) or R1Br (ethyl,
isopropyl), NaH, DMF, 0 °C to 60 °C, 2 h; (III) Br(CH2)nOH, K2CO3, DMF,
60 °C, 3 h; (IV) R2(CH2)nOH or g1 – g5, NaH, DMF, rt, 1 h; (V) Zn, NH4Cl,
CH3OH/H2O, rt, 2 h; (VI) NaH, DMF, N2, 85 °C, 16 h.
Supplementary data related to this article can be found online
at
References and notes
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Scheme 5. Synthesis of Target Compounds E23 – E26. Regents and
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°
°
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The polar 3-one group of isatin of the crystal structure 2XFP
is in a micro hydrophobic environment, and we had strongly
believed that chopping this polar group or changing it to nonpolar
(hydrophobic) ones would enhance the activity. On the basis of
this idea and principles of structure-based drug design, four
scaffolds followed up Scaffold A were designed. However, to our
surprise, none of the synthesized compounds demonstrated
improved affinity against hMAO-B. Their potency even was
worsened. For example, extending a (3,4-dichlorobenzyl)oxy
moiety from the 5 position of isatin produced compound A3,
which has excellent potency (IC50 = 0.003 μM) and isoform
selectivity (SI = 38,933) against hMAO-B. However, modifying
the 3-one to a nonpolar methyl group, which has similar size but
different charge distribution, led to a moderate hMAO-B
17. Tzvetkov NT, Stammler HG, Neumann B, Hristova S, Antonov L,