Synthesis and biological evaluation of novel 6-substituted 5-alkyl-2-(arylcarbonylmethylthio)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A novel series of 2-arylcarbonylmethylthio-6-arylmethylpyrimidin-4(3H)-ones have been synthesized and evaluated for in vitro anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC(50) range from 8.97 microM to 0.010 microM. Among them, the 6-(3,5-dimethylbenzyl) analogue 5p was identified as the most promising compound (EC(50)=0.010 microM, SI>31,800) associated with moderate activity against the HIV-1 double mutant RT strain K103N+Y181C. The structure-activity relationships of these new congeners were further discussed.     

Synthesis and biological evaluation of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors

We have developed a series of substituted 4-(thiophen-2-ylmethyl)-2H-phthalazin-1-ones as potent PARP-1 inhibitors. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to, or higher than AZD-2281. Among these compounds, 18q appeared to be the most notable one, which displayed an 8-fold improvement in enzymatic activity compared to AZD-2281. These efforts lay the foundation for our further investigation.     

Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1,6c6, and 6b1 (EC(50)=0.24 ± 0.05, 0.38 ± 0.13, 0.39 ± 0.05 μM, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50)=0.21 μM) and delavirdine (DLV) (EC(50)=0.32 μM). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies.     

Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors

PDK1 is an important regulator of the PI3K/Akt pathway, which has been found frequently activated in a large number of human cancers. Herein we described the preparation of novel substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. The synthesis is based around a Buchwald–Hartwig cross-coupling of various 3-bromo-6-substituted-quinolin-2(1H)-ones with three different functionalised anilines. The modular nature of the designed synthesis allowed access to a series of novel inhibitors through derivatisation of a late-stage intermediate. All compounds were screened against isolated PDK1 enzyme, with modest inhibition observed.     

Design,synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs

A novel series of 3-benzyloxy-linked pyrimidinylphenylamine derivatives (8a–8s) was designed, synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cell cultures. Most of the compounds inhibited wild-type (wt) HIV-1 replication in the lower micromolar concentration range (EC₅₀ = 0.05–35 μM) with high selectivity index (SI) values (ranged from 10 to >4870). In particular, 8h and 8g displayed excellent antiretroviral activity against wt HIV-1 with low cytotoxicity (EC₅₀ = 0.07 μM, CC₅₀ >347 μM, SI >4870; EC₅₀ = 0.05 μM, CC₅₀ = 42 μM, SI = 777, respectively), comparable to that of the marked drug nevirapine (EC₅₀ = 0.113 μM, CC₅₀ >15 μM, SI >133). In order to confirm the binding target, 8h was selected to perform the anti-HIV-1 RT assay. Additionally, preliminary structure activity relationship (SAR) analysis and molecular docking studies of newly synthesized compounds were also discussed, as well as the predicted physicochemical properties.     

Design,synthesis and biological evaluation of novel acetamide-substituted doravirine and its prodrugs as potent HIV-1 NNRTIs

A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC₅₀ value of 54.8?nM. Among them, the two most potent compounds 8i (EC₅₀?=?59.5?nM) and 8k (EC₅₀?=?54.8?nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC₅₀ values, being superior to lamivudine (3TC, EC₅₀?=?12.8?μM) and comparable to doravirine (EC₅₀?=?13?nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N?+?Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail.     

Synthesis and biological evaluation of novel 2-arylalkylthio-4-amino-6-benzyl pyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Novel 2-aryalkylthio-4-amino-6-benzylpyrimidines (3a–i), which can be considered as S-DABO and TMC-125 analogue hybrid molecules, have been designed and synthesized as inhibitors of HIV-1 RT. The results clearly indicated that the changes at the N₃/C₄ position of pyrimidine ring could affect the hydrogen bonds strength and number between N₃/C₄ and the Lys101 residue which are indispensable for anti-HIV-1 RT activity. The biological activity results are also in accordance with the docking study.     

Design, synthesis and pharmacological screening of a series of N1-(substituted) aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)-pyrimidin-4(3H)-ones as potential histamine H1-receptor antagonists

A series of N1-(substituted)aryl-5,7-dimethyl-2-(substituted)pyrido(2,3-d)pyrimidin-4(3H)-one was designed on the basis of the triangular pharmacophoric requirement of histamine H1-receptor antagonists. The designed series was synthesized by cyclo-condensation of monoaryl thiourea with ethyl cyanoacetate in the presence of dry HCl gas to give N1-(substituted aryl)-2-mercaptopyrimidine-4(3H)-one, which on cyclo-condensation with acetylacetone gave the pyridopyrimidinone. Further methylation of the mercapto group at C-2 with methyl iodide followed by nucleophilic displacement of the methylmercapto group by various amines gave the targeted compounds. All the synthesized compounds were screened for histamine H1-receptor antagonistic activity by the in vitro method of inhibition of the isotonic contraction induced by histamine on isolated guinea pig ileum using cetirizine as a standard drug. All the compounds exhibited potent histamine H1-receptor antagonistic activity with pA2 values from 7.30- 9.75 (cetirizine, pA2 value 9.40). The potent compounds were screened for their in vivo antihistaminic activity by protection of animal from asphyxic shock. The sedative potential of potent compounds was checked on albino mice by photoactometer and they had comparative sedative potential to the standard drug cetirizine. None of the compound exhibited anticholinergic activity in the in vitro rat ileum model.     

Synthesis and immunosuppressive activity evaluation of substituted N-imidazolidin-2-ones and N-tetrahydropyrimidin-2(1H)-ones

Seventeen compounds with either an imidazolin-2-one or a tetrahydropyrimidin-2(1H)-one scaffold were synthesized and evaluated for their immunosuppressive activity in a concanavallin A (ConA)-stimulated mouse splenocytes proliferation test. Three of these molecules exerted a significant activity at 90 microM. All the compounds of the tetrahydropyrimidin-2(1H)-one series have turned out to be inactive showing the crucial role of the imidazolidin-2-one scaffold in the induction of an immunosuppressive activity.     

Synthesis and immunosuppressive activity evaluation of substituted N-imidazolidin-2-ones and N-tetrahydropyrimidin-2(1H)-ones

Seventeen compounds with either an imidazolin-2-one or a tetrahydropyrimidin-2(1H)-one scaffold were synthesized and evaluated for their immunosuppressive activity in a concanavallin A (ConA)-stimulated mouse splenocytes proliferation test. Three of these molecules exerted a significant activity at 90 μM. All the compounds of the tetrahydropyrimidin-2(1H)-one series have turned out to be inactive showing the crucial role of the imidazolidin-2-one scaffold in the induction of an immunosuppressive activity.     

Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60 mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6 h at a dosage of 4.0 mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.     

Synthesis of substituted 5[H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors

1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC₅₀ values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring.     

Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitors

A series of C-6 or C-3' alkynyl-substituted 4-anilinoquinazoline derivatives was prepared straightforwardly by a Sonogashira reaction of the corresponding bromo-substituted 4-anilinoquinazolines. Bioactive assay of these compounds for in vitro EGFR kinase inhibition demonstrated that the novel 6-hydroxypropynyl-4-anilinoquinazoline 5e was a very potent EGFR kinase inhibitor with an IC(50) of 14 nM.     

Synthesis and biological evaluation of novel N-acyl substituted quinolin-2(1H)-one derivatives as potential antimicrobial agents

A series of novel N-acyl substituted quinolin-2(1H)-one derivatives were synthesized and screened in vitro for their antibacterial and antifungal activities by disc diffusion method. All the compounds exhibited moderate to good antimicrobial activities, some of these compounds displayed comparable or better antibacterial or antifungal activities against some tested strains compared to the reference drugs Streptomycin and Fluconazole.     

Design and synthesis of 2-(3-alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones as potent antitumor agents

2-(3-Alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones 1–3 were synthesized and screened for anti-proliferative activity against three human cancer cell lines, as well as the normal cell line Detroit 551. All of the synthesized target compounds 1–3 demonstrated potent cytotoxic activity against the cancer cell lines, but weak inhibitory activity toward the normal cell line. 2-(3-Methyl aminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (1), one of the potent compounds in vitro, was also tested in an in vivo Hep3B xenograft nude mice model, and its significant anticancer activity was reconfirmed. Therefore, compound 1 merits further investigation as an antitumor clinical trial candidate and potential anticancer agent.     

Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines (CAPYs) as HIV-1 NNRTIs

A series of 18 cycloalkyl arylpyrimidines (CAPYs) were designed from lead compounds diarylpyrimidines (DAPYs), synthesized and evaluated for in vitro anti-HIV activity. Among them, the compound 1p displayed potent anti-HIV-1 activity against WT HIV-1 with an EC(50) value of 0.055 μM and a selectivity index (SI) >7290. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated, which enriched the SAR of diarylpyrimidines (DAPYs).     

Synthesis and biological evaluation of 3-ethylidene-1,3-dihydro-indol-2-ones as novel checkpoint 1 inhibitors

Chk1 inhibitors have emerged as a novel class of neoplastic agents for abrogating the G2 DNA damage checkpoint arrest. Analogs of the Chk1 inhibitor, 3-ethylidene-1,3-dihydro-indol-2-one, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analog 28, which possesses potent enzymatic and cellular activities.