SYNTHESIS OF A PHENYLETHYLTHIOUREA DERIVATIVE AS A POTENTIAL NON-NUCLEOSIDE INHIBITOR OF HIV-1 REVERSE TRANSCRIPTASE

Abstract

The emergence of resistant strains of HIV-1 towards existing drugs has prompted a search for new compounds with good antiviral activity and favourable toxicological profile. This work reports the synthesis of a PETT derivative, N-[2-(4-Hydroxyphenyl)ethyl]-N’-[2-(5-bromopyridyl)]-thiourea (15), using 4-hydroxybenzaldehyde (14) as the starting reagent. This involved hydroxyl group protection of 14, followed by a Henry-Aldol condensation in to nitrostyrene 18, in 94% good yields. Subsequent reduction of the nitrostyrene and eventual Boc protection gave carbamate 20. This intermediate reagent 20 was then debenzylated via hydrogenolysis to form 21, which was then Boc deprotected to form a new aminophenol 22. The novel target compound 15 was furnished in 57% yield via a coupling reaction between the new phenol carbamate 21 and a thiocarbonyl derivative 6. X-ray diffraction structural determination of one of the intermediates, N-[(2(4-benzyloxyphenyl)ethyl]-tert-butylcarbamate, 20, displayed unit cell parameters a = 11.040(3) Å, b = 5.0931(12) Å, c = 64.070(16) Å, α= 90°, β= 94.493(14)°, γ = 90°, Z=8 and cell volume 3591.4(16) Å3. This compound was found to exist in discrete monomeric molecules held together by hydrogen bonds and other intermolecular interactions. Its two rings are not coplanar and each molecule showed a twisted conformation with angles between the least squares planes of the aromatic rings of (C16, C20, C2 and C6 = -15.8 (3) °. A docking model of the inhibitor into the NNIBP using AutoDock, revealed the formation of hydrogen-bonds between a thiocarbonyl group (C=S) of 15 and amino hydrogen of the Lys 101 side chain. Additionally, its stability was attributed to the π-π stacking interactions of its phenyl ring and the two aromatic rings of Tyr 181 and Tyr 188. This was evident in the estimated Free binding energy of -7.50 kcal/mol. The estimated Inhibition Constant, Ki of 15, was found to be 3.18 μM (Temperature = 298.15 K).