Sains Malaysiana 54(9)(2025): 2185-2199

http://doi.org/10.17576/jsm-2025-5409-07

 

Synthesis, Molecular Docking and Dynamic Studies of 3-Cyano-6-Hydroxy-5-Pentaloxy N-Boc Cyclohexene as Key Intermediate for Oseltamivir Phosphate

(Sintesis, Pendokan Molekul dan Dinamik 3-Siano-6-Hidroksi-5-Pentaloksi N-Boc Sikloheksena sebagai Perantara Penting bagi Oseltamivir Fosfat)

 

ZURHANA MAT HUSSIN¹, NAJMAH P.S HASAN², FAZNI SUSILA ABD GHANI², SHAARI DAUD¹, MOHD SALLEH ROFIEE^2,3, SYAHRUL IMRAN^2,4 & MOHD TAJUDIN MOHD ALI^2,*

 

¹Faculty of Applied Sciences, Universiti Teknologi MARA, Cawangan Pahang, 26400 Bandar Tun Abdul Razak, Pahang, Malaysia
²Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia
³Integrative Pharmacogenomics, Puncak Alam Campus, Universiti Teknologi MARA, 42300
Puncak Alam, Selangor, Malaysia
⁴Institute for Natural Product Discovery, Puncak Alam Campus, Universiti Teknologi MARA, 42300
Puncak Alam, Selangor, Malaysia

 

Received: 9 April 2025/Accepted: 18 July 2025

 

Abstract

A key intermediate for oseltamivir phosphate synthesis, compound 15 (3-cyano-6-hydroxy-5-pentaloxy-N-Boccyclohexene), was synthesized from inexpensive, commercially available 1,4-cyclohexadiene (4). The synthesis involved eight steps, sequentially introducing substituents onto a cyclohexene ring: An amino group at C1, hydroxy at C6, pentaloxy at C5, and cyano at C3. C1 amination was achieved via epoxidation and asymmetric ring opening using a salen complex and TMSN₃. The C6 hydroxy group was introduced via one-pot reduction and amine protection. C5 functionalization involved allylic oxidation (SeO₂/TBHP) and etherification with 3-pentanol. The C3 cyano group was formed via olefin epoxidation, TMSCN ring opening, and elimination. Molecular docking showed compound 15 had a binding energy of -7.14 kcal/mol, comparable to oseltamivir (-8.5 kcal/mol), suggesting strong neuraminidase binding. A 200 ns molecular dynamics simulation confirmed complex stability, with RMSF analysis indicating stable interactions. The ADMET profile indicates that these compounds exhibit good drug-like properties, including high gastrointestinal (GI) absorption, good solubility, and no inhibition of CYP450 enzymes.

 

Keywords: Dynamic; epoxidation; neuraminidase; oseltamivir; salen catalyst

 

Abstrak

Sebatian perantaraan utama untuk sintesis oseltamivir fosfat, sebatian 15 (3-siano-6-hidroksi-5-pentaloksi-N-Boccyclohexene), telah disintesis daripada 1,4-sikloheksadiena (4) yang murah dan tersedia secara komersial. Sintesis ini melibatkan lapan langkah dengan kumpulan pengganti diperkenalkan secara berurutan ke atas gelang sikloheksena: kumpulan amino pada karbon-1, hidroksi pada karbon-6, pentaloksi pada karbon-5 dan siano pada karbon-3. Penggabungan kumpulan amino pada C1 dicapai melalui tindak balas epoksidasi dan pembukaan gelang tak simetri menggunakan kompleks salen dan TMSN₃. Kumpulan hidroksi pada C6 diperkenalkan melalui penurunan satu langkah dan perlindungan amina. Penggantian pada C5 melibatkan pengoksidaan alilik (SeO₂/TBHP) dan eterifikasi dengan 3-pentanol. Kumpulan siano pada C3 dibentuk melalui epoksidasi olefin, pembukaan gelang dengan TMSCN dan tindak balas penyingkiran. Kajian pendokan molekul menunjukkan sebatian 15 mempunyai tenaga pengikatan sebanyak –7.14 kcal/mol, setanding dengan oseltamivir (-8.5 kcal/mol), menunjukkan ikatan yang kuat dengan tapak aktif neuraminidase. Simulasi dinamik molekul selama 200 ns mengesahkan kestabilan kompleks, dengan analisis RMSF menunjukkan interaksi yang stabil. Profil ADMET menunjukkan sebatian-sebatian ini memenuhi ciri ubat yang baik, termasuk penyerapan gastrousus (GI) yang tinggi, keterlarutan yang baik dan tiada perencatan enzim CYP450.

 

Kata kunci: Dinamik; epoksidasi; mangkin salen; neuraminidase; Oseltamivir

 

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*Corresponding author; email: tajudinali@uitm.edu.my