Geometrically and Conformationally Restrained Cinnamoyl Compounds as Inhibitors of HIV-1 Integrase:  Synthesis, Biological Evaluation, and Molecular Modeling

Abstract

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.

On the Importance of the Aromatic Ring Parameter in Studies of the Solvolyses of Cinnamyl and Cinnamoyl Halides

“…The 3-D images of 3’ and 5’ clearly attests to the planar conformation between the aromatic ring, the vinylic double bond, and the carbonyl group. Studies have shown that when cinnamoyl-based structures were synthesized and characterized by a syn disposition of the carbonyl group with the vinylic double bond, they specifically inhibited the enzymatic reactions associated with HIV-1 integrase (IN) [36]. …”

Synthesis and structure of some (E)-ferrocene-methylenecycloalkanones and their benzylidene analogs

“…26 In the cyclohexanone (6b) and the cycloheptanone (6c) derivatives the molecules are more distorted and the conformers with out of plane aryl group to the C=C double bonds are preferred. 27,6 The stereostructure is practically the same in the 4 and the 7-11-type dienones. In the monosubstituted cyclanones 5 the cinnamoyl moiety is distorted even in the molecules of 5a with 5-membered ring: in the solid state the plane of the aryl ring deviates from that of the C=C double bond by 23 º .…”

“…1 Previously, we described the preparation of saturated and partially saturated 1,3-thiazines using E-2-arylidenecycloalkanones as starting materials. 2,3 Some diarylidenecycloalkanones have been reported to possess cytoprotective 4,5 as well as HIV-1 integrase 6 and factor Xa inhibitor activities 7 . These effects were found to depend on the ring size (stereochemistry) and the substituents of the aromatic rings.…”

Synthesis and Anti-Tumor Activity of Novel Aminomethylated Derivatives of Isoliquiritigenin

“…In our present study, chalcone was first synthesized by a hydroxyl-protection method and a consequent condensation reaction was performed in a base environment [27,28]. Then, different nitrogen atoms side chains (heterocyclic azo and open chain amino) were attached to the A ring by Mannich reactions.…”