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. 2018;17(Suppl2):65-77.

Design, Synthesis, Molecular Modeling, In Silico ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives

Zeynab Alimi Livani  1 , Mahdieh Safakish  2 , Zahra Hajimahdi  2 , Sepehr Soleymani  3 , Rezvan Zabihollahi  3 , Mohammad Reza Aghasadeghi  3 , Eskandanr Alipour  1 , Afshin Zarghi  2
Affiliations

Design, Synthesis, Molecular Modeling, In Silico ADME Studies and Anti-HIV-1 Assay of New Diazocoumarin Derivatives

Zeynab Alimi Livani et al. Iran J Pharm Res. 2018.

Abstract

Some new diazo incorporated coumarin compounds were designed and synthesized to evaluate their anti-HIV activity. Overall, compounds were active against HIV at 100 μM. Additionally, no cytotoxic effect was observed at this concentration. The compound with 4-chlorobenzyl group indicated the best anti-HIV activity (52%). Docking studies using the later crystallographic data available for PFV integrase showed similar binding modes to HIV-1 integrase inhibitors. On the basis of these data, nitrogen atoms of 1,3,4-oxadiazole ring have been involved in the Mg2+ chelation and 4-chlorobenzyl group occupies the same position as 4-flourobenzyl group of raltegravir in the active site. In addition, in silico ADME assay demonstrated favorable physicochemical properties for the new designed compounds. Thus, synthesized structures could be introduced as a novel template for designing safe anti-HIV compounds with integrase inhibitory potential.

Keywords: 1; 3; 4-Oxadiazole; ADME; Anti-HIV; Diazocoumarin; Docking; Synthesis.

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Figures

Figure 1
Figure 1
FDA-approved INSTIs
Figure 2
Figure 2
Lead anti-HIV compounds (1, 2, 3 and FP-21399) and our designed structure
Scheme 1
Scheme 1
Reagents and conditions: (a) ethanol, sulfuric acid, reflux, 24h (b) ethanol, NH2-NH2.OH (6 eq.), reflux, 96h (c) ethanol, CS2, KOH, reflux, 4h (d) methanol, 10% aq. NaOH, substituted alkyl/aryl halides, r.t (e) 1. 6M hydrochloric acid 2. 10% sodium nitrite, 0-5 °C (f) 10% aq. Na2CO3, stir, 0-5 °C
Figure 3
Figure 3
(a) 2D alignment of best docked conformer of compound 11f and (b) 3D alignment of best docked conformer of compound11f (shown in pink) in the PFV IN active site
Figure 4
Figure 4
(a) Superimposition of compound 11f (shown in pink) on raltegravir (shown in yellow) in the PFV IN active site. (b) Interaction of compound 11f (shown in pink) and raltegravir (shown in yellow) with the surface of PFV IN active site designated with aromatic property
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