22032-65-1Relevant articles and documents
Design, synthesis and diversification of natural product-inspired hydantoin-fused tetrahydroazepino indoles
Barve, Indrajeet J.,Dalvi, Prashant B.,Thikekar, Tushar Ulhas,Chanda, Kaushik,Liu, Yu-Li,Fang, Chiu-Ping,Liu, Chia-Chen,Sun, Chung-Ming
, p. 73169 - 73179 (2015)
A facile and efficient synthesis of novel oxo, thio and seleno hydantoin fused tetrahydroazepino [4,5-b]indoles was reported. A naturally occurring iboga class alkaloid inspired seven-membered azepino[4,5-b]indole ring was synthesized as a new scaffold through Pictet-Spengler reaction followed by skeletal rearrangement of the aziridine ring. To improve the efficiency of the synthetic route, the double bond of the rearranged olefinic product 5 was reduced and a privileged hydantoin moiety was constructed on the core system through urea formation using a variety of isocyanates, isothiocyanates and isoselenocyanates followed by intramolecular cyclization to incorporate elements of diversity. The regeneration of the double bond of intermediate 9 afforded hydantoin-fused tetrahydroazepino [4,5-b]indoles.
Design of novel β-carboline derivatives with pendant 5-bromothienyl and their evaluation as phosphodiesterase-5 inhibitors
El-Gamil, Dalia S.,Ahmed, Nermin S.,Gary, Bernard D.,Piazza, Gary A.,Engel, Matthias,Hartmann, Rolf W.,Abadi, Ashraf H.
, p. 23 - 33 (2013)
New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. The following SAR can be concluded: The tetracyclic scaffold is essential for PDE5 inhibition; the ethyl group is the most suitable among the adopted N-substituents on the terminal ring (hydantoin/ piperazinedione); the appropriate stereochemistry of C-5/C-6 derived from the aldehyde rather than C-11a/C-12a derived from tryptophan appears crucial for inhibition of PDE5; surprisingly, derivatives with the hydantoin terminal ring are more active than their analogs with the piperazinedione ring; the selectivity versus PDE5 relative to PDE11 with cGMP as a substrate is mainly a function of the substitution and stereochemistry pattern of the external ring, in other words of the interaction with the H-loop residues of the isozymes. Thirteen derivatives showed PDE5 inhibitory activity with IC50 values in the range of 0.16-5.4 μm. Compound 8 was the most potent PDE5 inhibitor and showed selectivity towards PDE5 versus other PDEs, with a selectivity index of 49 towards PDE5 rather than PDE11 with cGMP as the substrate. New derivatives with the tetrahydro-β-carboline-imidazolidinedione and tetrahydro-β-carboline-piperazinedione scaffolds and a pendant bromothienyl moiety at C-5/C-6 were synthesized and tested for their ability to inhibit PDE5 in vitro. Of these, 13 derivatives showed PDE5 inhibitory activity with IC 50 values in the range of 0.16-5.4 μm and with compound 8 being the most active derivative. The tetracyclic scaffold was shown to be essential for PDE5 inhibition. Copyright
Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel β-carboline derivatives
Ahmed, Nermin S.,Ali, Amal H.,El-Nashar, Shreen M.,Gary, Bernard D.,Fajardo, Alexandra M.,Tinsley, Heather N.,Piazza, Gary A.,Negri, Matthias,Abadi, Ashraf H.
, p. 329 - 343 (2012)
By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-β-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking.
Total Synthesis of Homo-and Heterodimeric Bispyrrolidinoindoline Dioxopiperazine Natural Products
álvarez, Rosana,Alvarez, Susana,Areal, Andrea,De Lera, ángel R.,Domínguez, Marta,Vendrig, Pim
supporting information, p. 1725 - 1737 (2021/06/28)
Total synthesis and structural confirmation of homo-and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N′-bis-demethylated analogue (+)-12, (-)-dibrevianamide F (13), (-)-SF-5280-451 (14), tetratryptomycin A (15), (-)-Tryprophenaline (17), and (-)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-Triazepan-6-one heterocycle.
An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4
Samuels, Eric R.,Sevrioukova, Irina F.
, (2020/02/13)
Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R1 side-group as phenyl or naphthalene and R2 as indole or naphthalene in different stereo configuration showed that (i) analogues with the R2-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R2-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055–0.085 μM vs. 0.130 μM, respectively).
