159005-71-7Relevant articles and documents
Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants
Zhu, Mei,Ma, Ling,Zhou, Huiyu,Dong, Biao,Wang, Yujia,Wang, Zhen,Zhou, Jinming,Zhang, Guoning,Wang, Juxian,Liang, Chen,Cen, Shan,Wang, Yucheng
, (2020)
Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2′ ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.
Design, synthesis and biological evaluation of novel HIV-1 protease inhibitors with pentacyclic triterpenoids as P2-ligands
Zhu, Mei,Du, Xiao-Nan,Li, Yun-Ge,Zhang, Guo-Ning,Wang, Ju-Xian,Wang, Yu-Cheng
, p. 357 - 361 (2019)
The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2′ ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 μM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 μM).
Rational design and Structure?Activity relationship of coumarin derivatives effective on HIV-1 protease and partially on HIV-1 reverse transcriptase
Zhu, Mei,Ma, Ling,Wen, Jiajia,Dong, Biao,Wang, Yujia,Wang, Zhen,Zhou, Jinming,Zhang, Guoning,Wang, Juxian,Guo, Ying,Liang, Chen,Cen, Shan,Wang, Yucheng
, (2020)
Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC50 values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC50 values of 241.8 and 188.7 μM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.
Novel HIV-1 Protease Inhibitors with Morpholine as the P2 Ligand to Enhance Activity against DRV-Resistant Variants
Cen, Shan,Dong, Biao,Dou, Yue,Ma, Ling,Wang, Juxian,Wang, Yucheng,Zhang, Fan,Zhang, Guoning,Zhou, Jinming,Zhu, Mei
, p. 1196 - 1204 (2020)
Flexible heterocyclic moieties as the P2 ligands of HIV-1 protease inhibitors may be adapted to the minimally distorted active site of mutations easily and enhance activity against DRV-resistant HIV-1 variants. Herein, the design, synthesis, and biological evaluation of a new series of inhibitors containing morpholine derivatives as the P2 ligands were described, among which, carbamate inhibitor 23a and carbamido inhibitor 27a exhibited almost 4- and 2-fold superior activity with enzyme Ki of 0.092 nM and 0.21 nM, as well as antiviral IC50 values of 0.41 nM and 0.95 nM, respectively, compared to DRV. Besides, they exhibited excellent activity with inhibition of 94percent and 91percent, respectively. Furthermore, they also showed appreciable antiviral activity against DRV-resistant HIV-1 variants.
(Hydroxyethyl) sulfonamide HIV-1 protease inhibitors: Identification of the 2-methylbenzoyl moiety at P-2
Freskos,Bertenshaw,Getman,Heintz,Mischke,Blystone,Bryant,Funckes-Shippy,Houseman,Kishore,Kocan,Mehta
, p. 445 - 450 (1996)
We have discovered a potent low molecular weight series of HIV-1 protease inhibitors incorporating the (R)-(hydroxyethyl) sulfonamide isostere.
Accessing HIV-1 Protease Inhibitors through Visible-Light-Mediated Sequential Photocatalytic Decarboxylative Radical Conjugate Addition-Elimination-Oxa-Michael Reactions
Bhattacharyya, Aditya,Krolo, Tomislav,Reiser, Oliver
, p. 6283 - 6287 (2021/08/23)
A photocatalytic decarboxylative radical conjugate addition-elimination-oxa-Michael reaction of hydroxyalkylated carboxylic acids with cyclopentenones is developed to construct diverse cyclopentanonyl-fused functionalized 5-7 membered cyclic ethers. The stereoselective synthetic strategy is amenable to substructural variation, establishing a direct total synthetic route to two diastereomers of C3-amino cyclopentyltetrahydrofuranyl-derived potent HIV-1 protease inhibitors with low nanomolar IC50 values.
Design and biological evaluation of cinnamic and phenylpropionic amide derivatives as novel dual inhibitors of HIV-1 protease and reverse transcriptase
Zhu, Mei,Shan, Qi,Ma, Ling,Wen, Jiajia,Dong, Biao,Zhang, Guoning,Wang, Minghua,Wang, Juxian,Zhou, Jinming,Cen, Shan,Wang, Yucheng
, (2021/05/04)
Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 μM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.
Design and evaluation of novel piperidine HIV-1 protease inhibitors with potency against DRV-resistant variants
Zhu, Mei,Zhou, Huiyu,Ma, Ling,Dong, Biao,Zhou, Jinming,Zhang, Guoning,Wang, Minghua,Wang, Juxian,Cen, Shan,Wang, Yucheng
, (2021/06/02)
A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2’ ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4?3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.
Nitrogen-containing heterocyclic amino derivative, preparation method thereof and anti-HIV-1 medicine
-
, (2021/08/21)
The invention provides a nitrogen-containing heterocyclic ring amino derivative, a preparation method thereof and an anti-HIV-1 medicine, and belongs to the technical field of medicine application. The nitrogen-containing heterocyclic ring amino derivative provided by the invention can interfere with the process of hydrolyzing Gap and Gap-Pol precursor polyprotein by HIV-1 protease, and has high HIV-1 protease inhibitory activity; meanwhile, the nitrogen-containing heterocyclic ring amino derivative provided by the invention has remarkable inhibitory activity on wild type anti-HIV-1 medicine strains and high anti-DRV-medicine strains, has low cytotoxicity, and has a good application prospect as an anti-AIDS medicine.
New heteroaryl carbamates: Synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors
Tramutola, Francesco,Armentano, Maria Francesca,Berti, Federico,Chiummiento, Lucia,Lupattelli, Paolo,D'Orsi, Rosarita,Miglionico, Rocchina,Milella, Luigi,Bisaccia, Faustino,Funicello, Maria
, p. 1863 - 1870 (2019/03/27)
New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors.
