Design,synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors

A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC₅₀ less than 20 nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC₅₀: 1.4 ± 0.1 nM) and cytotoxicities with IC₅₀ values at 13.9 ± 1.8 nM and 9.5 ± 0.5 nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27–29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs.     

Structure–activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists

On the basis of potent and selective binding affinity of truncated 4′-thioadenosine derivatives at the human A₃ adenosine receptor (AR), their bioisosteric 4′-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-d-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N⁶ positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A₃ AR. They were less potent than the corresponding 4′-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X = Cl, R = 3-bromobenzyl) showed the highest binding affinity (K_i = 13.0 ± 6.9 nM) at the hA₃ AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4′-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA₃ AR-expressing CHO cells. Although the 4′-oxo series were less potent than the 4′-thio series, this class of human A₃ AR antagonists is also regarded as another good template for the design of A₃ AR antagonists and for further drug development.     

Structural modifications of CH(OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors

A series of CR₂(OH)-diarylpyrimidine derivatives (CR₂(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC₅₀ values ranging from 7.21 ± 1.99 to 0.067 ± 0.006 μM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC₅₀ = 0.067 ± 0.006 μM, SI > 592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated.     

Search for novel histone deacetylase inhibitors. Part II: Design and synthesis of novel isoferulic acid derivatives

Previously, we described the discovery of potent ferulic acid-based histone deacetylase inhibitors (HDACIs) with halogeno-acetanilide as novel surface recognition moiety (SRM). In order to improve the affinity and activity of these HDACIs, twenty seven isoferulic acid derivatives were described herein. The majority of title compounds displayed potent HDAC inhibitory activity. In particular, IF5 and IF6 exhibited significant enzymatic inhibitory activities, with IC₅₀ values of 0.73 ± 0.08 and 0.57 ± 0.16 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against human cancer cells. Especially, IF6 displayed promising profile as an antitumor candidate with IC₅₀ value of 3.91 ± 0.97 μM against HeLa cells. The results indicated that these isoferulic acid derivatives could serve as promising lead compounds for further optimization.     

Design,synthesis and biological evaluation of novel coumarin thiazole derivatives as α-glucosidase inhibitors

A new series of coumarin thiazole derivatives 7a-7t were synthesized, characterized by ¹H NMR, ¹³C NMR and element analysis, evaluated for their α-glucosidase inhibitory activity. The majority of the screened compounds displayed potent inhibitory activities with IC₅₀ values in the range of 6.24 ± 0.07–81.69 ± 0.39 μM, when compared to the standard acarbose (IC₅₀ = 43.26 ± 0.19 μM). Structure–activity relationship (SAR) studies suggest that the pattern of substitution in the phenyl ring is closely related to the biological activity of this class of compounds. Among all the tested molecules, compound 7e (IC₅₀ = 6.24 ± 0.07 μM) was found to be the most active compound in the library of coumarin thiazole derivatives. Enzyme kinetic studies showed that compound 7e is a non-competitive inhibitor with a K_i of 6.86 μM. Furthermore, the binding interactions of compound 7e with the active site of α-glucosidase were confirmed through molecular docking. This study has identified a new class of potent α-glucosidase inhibitors for further investigation.     

Synthesis,cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives

Alzheimer’s disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC₅₀ value of 0.04 ± 0.01 μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC₅₀ value of 0.06 ± 0.02 μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.     

Thieno[2,3-b]pyridines—A new class of multidrug resistance (MDR) modulators

To identify new potent multidrug resistance modulators, we have synthesized a series of novel thieno[2,3-b]pyridines and furo[2,3-b]pyridines, and examined their stucture–activity relationships. All synthesized compounds were tested to determine BCRP1, P-gp, and MRP1 inhibitor activity, and most potent MDR modulators were also screened for their toxicity, cytotoxicity and Ca²⁺ channel antagonist activity. Among these compounds, thieno[2,3-b]pyridine (6r) was found to exhibit a potent P-gp inhibitory action with EC₅₀ = 0.3 ± 0.2 μM, MRP1 inhibitory action with EC₅₀ = 1.1 ± 0.1 μM and BCRP1 inhibitory action with EC₅₀ = 0.2 ± 0.05 μM and may represent suitable candidate for further pharmacological studies.     

Synthesis,in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase

A series of thiazole derivatives 1–21 were prepared, characterized by EI-MS and ¹H NMR and evaluated for α-glucosidase inhibitory potential. All twenty one derivatives showed good α-glucosidase inhibitory activity with IC₅₀ value ranging between 18.23 ± 0.03 and 424.41 ± 0.94 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Compound (8) (IC₅₀, 18.23 ± 0.03 μM) and compound (7) (IC₅₀ = 36.75 ± 0.05 μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of α-glucosidase inhibitors.     

Thiadiazole derivatives as New Class of β-glucuronidase inhibitors

Thiadiazole derivatives 1–24 were synthesized via a single step reaction and screened for in vitro β-glucuronidase inhibitory activity. All the synthetic compounds displayed good inhibitory activity in the range of IC₅₀ = 2.16 ± 0.01–58.06 ± 1.60 μM as compare to standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Molecular docking study was conducted in order to establish the structure–activity relationship (SAR) which demonstrated that thiadiazole as well as both aryl moieties (aryl and N-aryl) involved to exhibit the inhibitory potential. All the synthetic compounds were characterized by spectroscopic techniques ¹H, ¹³C NMR, and EIMS.     

Design,synthesis, and preliminary studies of the activity of novel derivatives of N-cinnamoyl-l-aspartic acid as inhibitors of aminopeptidase N/CD13

A series of novel derivatives of N-cinnamoyl-l-aspartic acid were designed, synthesized, and assayed for their inhibitory activities against aminopeptidase N. The preliminary biological assay showed that compound 8c has the most potent inhibitory activity against APN with an IC₅₀ of 11.1 ± 0.9 μM, this could be used as the lead compound in future research on anticancer agents.     

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC₅₀: 0.68 ± 0.13 μM) with strong DPPH and ABTS radical scavenging activity (IC₅₀: 13.77 ± 0.25 μM and IC₅₀: 12.59 ± 0.21 μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC₅₀: 0.74 ± 0.09 μM) and with DPPH and ABTS radical scavenging activity (IC₅₀: 13.52 ± 0.62 μM and IC₅₀: 13.13 ± 0.85 μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.     

Design and synthesis of N6-substituted-4′-thioadenosine-5′-uronamides as potent and selective human A3 adenosine receptor agonists

On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA (N⁶-(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β-d-ribofuranosyl)adenine), which is a potent and selective A₃ adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue (5h) of IB-MECA showed extremely high binding affinity (K_i = 0.25 nM) at the human A₃AR and was more potent than IB-MECA (K_i = 1.4 nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A₃AR binding, although small alkyl analogues were more potent.     

Synthesis,molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor

Thiourea derivatives having benzimidazole 1–17 have been synthesized, characterized by ¹H NMR, ¹³C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker’s yeast α-glucosidase enzyme. Compounds 1–17 exhibited a varying degree of α-glucosidase inhibitory activity with IC₅₀ values between 35.83 ± 0.66 and 297.99 ± 1.20 μM which are more better than the standard acarbose (IC₅₀ = 774.5 ± 1.94 μM). Compound 10 and 14 showed significant inhibitory effects with IC₅₀ value 50.57 ± 0.81 and 35.83 ± 0.66 μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.     

Discovery of simplified N2-substituted pyrazolo[3,4-d]pyrimidine derivatives as novel adenosine receptor antagonists: Efficient synthetic approaches,biological evaluations and molecular docking studies

In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A₃ adenosine receptor (hA₃AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure–activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl–alkyl) functions were introduced at N² position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C⁶ position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA₃AR, as indicated by the low micromolar range of K_i values and among them, compound 63 with N² neopentyl substituents showed most potent hA₃AR affinity with K_i value of 0.9 μM and high selectivity (hA₁AR/hA₃AR = >111 & hA_2AAR/hA₃AR = >111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N² position displayed high affinity at another receptor subtype (hA_2AAR, e.g., compound 55, with K_i hA_2AAR = 0.8 μM), while they were less favorable at the hA₃AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA₃AR and hA_2AAR. Overall, PP derivatives represent promising starting points for new AR antagonists.     

Synthesis,in vitro β-glucuronidase inhibitory activity and in silico studies of novel (E)-4-Aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazoles

Current research is based on the synthesis of novel (E)-4-aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazole derivatives (3–15) by adopting two steps route. First step was the condensation between the pyrene-1-carbaldehyde (1) with the thiosemicarbazide to afford pyrene-1-thiosemicarbazone intermediate (2). While in second step, cyclization between the intermediate (2) and phenacyl bromide derivatives or 2-bromo ethyl acetate was carried out. Synthetic derivatives were structurally characterized by spectroscopic techniques such as EI-MS, ¹H NMR and ¹³C NMR. Stereochemistry of the iminic double bond was confirmed by NOESY analysis. All pure compounds 2–15 were subjected for in vitro β-glucuronidase inhibitory activity. All molecules were exhibited excellent inhibition in the range of IC₅₀ = 3.10 ± 0.10–40.10 ± 0.90 μM and found to be even more potent than the standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.38 ± 1.05 μM). Molecular docking studies were carried out to verify the structure-activity relationship. A good correlation was perceived between the docking study and biological evaluation of active compounds.     

A concise synthesis and evaluation of new malonamide derivatives as potential α-glucosidase inhibitors

A series of new malonamide derivatives were synthesized by Michael addition reaction of N¹,N³-di(pyridin-2-yl)malonamide into α,β-unsaturated ketones mediated by DBU in DCM at ambient temperature. The inhibitory potential of these compounds in vitro, against α-glucosidase enzyme was evaluated. Result showed that most of malonamide derivatives were identified as a potent inhibitors of α-glucosidase enzyme. Among all the compounds, 4K (IC₅₀ = 11.7 ± 0.5 μM) was found out as the most active one compared to standard drug acarbose (IC₅₀ = 840 ± 1.73 μM). Further cytotoxicity of 4a–4m were also evaluated against a number of cancer and normal cell lines and interesting results were obtained.     

Design,synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors

Two series of thiazolidinone derivatives designing for potential EGFR and HER-2 kinase inhibitors have been discovered. Some of them exhibited significant EGFR and HER-2 inhibitory activity. Compound 2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)thiazol-4(5H)-one (12) displayed the most potent inhibitory activity (IC₅₀ = 0.09 μM for EGFR and IC₅₀ = 0.42 μM for HER-2), comparable to the positive control erlotinib. Docking simulation was performed to position compound 12 into the EGFR active site to determine the probable binding model. Antiproliferative assay results indicating that some of the thiazolidinone derivatives own high antiproliferative activity against MCF-7. Compound 12 with potent inhibitory activity in tumor growth inhibition would be a potential anticancer agent.     

Design,synthesis and evaluation of novel metalloproteinase inhibitors based on l-tyrosine scaffold

A series of novel l-tyrosine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and histone deacetylase 8 (HDAC-8). The results showed that these l-tyrosine derivatives exhibited inhibitory profiles against MMP-2 and HDAC-8. The compounds 6h (IC₅₀ = 0.013 ± 0.001 μM) and 6j (IC₅₀ = 0.017 ± 0.001 μM) were equal potent MMP-2 inhibitors to the positive control NNGH (IC₅₀ = 0.014 ± 0.001 μM). As for HDAC-8 inhibition, some of the hydroxamate compounds, such as 6d (IC₅₀ = 3.6 ± 0.2 μM) and 6c (IC₅₀ = 5.8 ± 0.5 μM), were equal potent to the positive control SAHA (IC₅₀ = 1.6 ± 0.1 μM). Structure–activity relationships were also briefly discussed.     

Synthesis and in silico studies of novel sulfonamides having oxadiazole ring: As β-glucuronidase inhibitors

Novel sulfonamides having oxadiazole ring were synthesized by multistep reaction and evaluated to check in vitro β-glucuronidase inhibitory activity. Luckily, except compound 13, all compounds were found to demonstrate good inhibitory activity in the range of IC₅₀ = 2.40 ± 0.01–58.06 ± 1.60 μM when compared to the standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Structure activity relationship was also presented. However, in order to ensure the SAR as well as the molecular interactions of compounds with the active site of enzyme, molecular docking studies on most active compounds 19, 16, 4 and 6 was carried out. All derivatives were fully characterized by ¹H NMR, ¹³C NMR and EI-MS spectroscopic techniques. CHN analysis was also presented.