Synthesis of N-ω-Phenylalkyl-4-(p-chlorophenyl)-piperidin-4-ol Analogues with Potent Antiproliferative Activity Against HCT-116 Cells

Hatae, Noriyuki; Yoshimura, Teizo; Kujime, Eiko; Yano, Keigo; Kizuka, Mami; Ashida, Rina; Choshi, Tominari; Nishiyama, Takashi; Okada, Chiaki; Iwamura, Tatsunori

doi:10.3987/com-18-s(t)25

Cited by 1 publication

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“…Carboxylic acids 10a,b were prepared according to the procedures reported by Behrendt et al , First, the known but commercially unavailable phenylalkyl chlorides 7f – j were synthesized by an Appel reaction of the corresponding primary alcohols based on previously reported procedures (Supporting Information). , Alkylation of N -Boc-protected- O -benzyl hydroxylamine 6 , with phenylalkyl chlorides 7a – j in the presence of NaH in DMF provided the phenylalkoxy carbamates 8a – j . Subsequent deprotection of 8a – j with either TFA/DCM ( 9a – d ) or HCl/dioxane ( 9e – j ) provided the required N -substituted O -benzyl-protected hydroxylamines 9a – j (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR)

Abdullaziz,

Takada,

Illarionov

et al. 2024

ACS Infect. Dis.

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Reverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-D-xylulose 5phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum. Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar Pf DXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the N-phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N-terminal domain. As shown for reverse carba and thia analogs, Pf DXR selectively binds the S-enantiomer of the new lead compound. In addition, some representatives of the novel inhibitor subclass are nanomolar Escherichia coli DXR inhibitors, whereas the inhibition of Mycobacterium tuberculosis DXR is considerably weaker.

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