Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors

A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC₅₀ values of 0.005 and 0.009 μM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC₅₀ value of 8.2 μM. The preliminary structure–activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated.     

Synthesis and biological evaluation of some novel N-aryl-1,4-dihydropyridines as potential antitubercular agents

1,4-Dihydropyridines are the emerging class of antitubercular agent. Recently, studies have revealed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have demonstrated excellent antitubercular activity. We have synthesized new N-aryl-1,4-dihydropyridines bearing carbethoxy and acetyl group at C-3 and C-5 of the DHP ring. In addition, 1H-pyrazole ring is substituted at C-4 position. The lowest minimum inhibitory concentration value, 0.02 μg/mL, was found for diethyl 1-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)pyridine-3,5-dicarboxylate 4e making it more potent than first line antitubercular drug isoniazid. In addition, this compound exhibited relatively low cytotoxicity.     

Synthesis and biological evaluation of novel exo-methylene cyclopentanone tetracyclic diterpenoids as antitumor agents

The structure of exo-methylene cyclopentanone, which exists in nature tetracyclic diterpenoids products, has been proved to be an innate group for the treatment of cancer and inflammation. In this letter, four different scaffolds of tetracyclic diterpenoids including the structure exo-methylene cyclopentanone were synthesized from steviol and isosteviol and evaluated in vitro for their antitumor activity against three human cancer lines. Compounds 1a, 1b, 2b and 3b showed significant cytotoxicity, particularly, tetracyclic diterpenoids 2b, 3b were identified as the most potent and selective anticancer agents superior to adriamycin with IC₅₀ values of 0.9 μM and 1.5 μM, against Hep-G2 and MDA-MB-231 cell lines, respectively.     

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.     

Synthesis and biological evaluation of novel antiviral agents as protein–protein interaction inhibitors

Abstract

In continuation of our research efforts toward the identification and optimization for novel inhibitors of interaction between human immunodeficiency virus type 1 integrase and cellular cofactor LEDGF/p75, we designed and synthesized a new series of 4-benzylindole derivatives. Most of the title compounds proved to be able to block this protein–protein interaction (PPI), with a percentage ranging from 30% to 90% at 100?µM. The most promising derivative was compound 10b showing IC₅₀ value of 6.41?µM. The main structure–activity relationships (SAR) are discussed and rationalized by docking studies.     

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 pazopanib derivatives as antitumor agents

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.     

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.     

Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents

We have designed, synthesized, and evaluated as potential antitumor agents a series of 2-hydroxybenzylidene derivatives of the N-(2-trifluoromethylpiridyn-4-yl)anthranilic acid hydrazide, and some analogues bearing a (2-trifluoromethyl)piridyn-4-ylamino group in 3- or 4-position of benzohydrazide or 4-position of phenylacetohydrazide. Compounds 12e, 13e, 15e, and 16e, bearing a 4-(diethylamino)salicylidene group exhibited potent cytotoxicity, with averaged GI₅₀ values in sub-micromolar range, and a variety of cell selectivity at nanomolar concentrations. The determination of acute toxicity in athymic nudes mice proved some compounds to be non-toxic, making them good candidates for further study as antitumor agents.     

Synthesis and preliminary biological evaluation of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives as potential antimycobacterial agents: an operational Topliss Tree approach

A series of novel N-(3-aryl-1,2,4-triazol-5-yl) cinnamamide derivatives were designed on basis of structural similarity to the known FAS II inhibitors. Topliss operational method was used to optimize the potency of molecules. The minimum inhibitory concentration (MIC) of all synthesized compounds was determined against Mycobacterium tuberculosis H(37)R(v) using resazurin microtitre assay (REMA) plate method. The synthesized compounds exhibit antimycobacterial activity in the range of 5-95μM with a good safety profile.     

Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of novel thiazolidin-4-one analogues, characterized by different substitution patterns at positions C-2 and N-3 of the thiazolidin-4-one scaffold for anti-HIV-1 activity has been investigated. Most of the compounds showed anti-HIV-1 activity at micromolar concentrations when tested in TZM-bl cells in vitro. Among the thirty-three compounds tested, compound 16 was the most potent inhibitor of HIV-1 replication against HIV-1_IIIB, HIV-1_ADA5, HIV-1_UG070 and HIV-1_VB59 (EC₅₀ = 0.02, 0.08, 0.08 and 0.08 μM, respectively) with selectivity index (SI = 6940, 1735, 1692 and 1692) against tested viral strains, respectively. The results of the present study suggested that the substitution of the nitro group at 6′ position of the C-2 phenyl ring and 4,6-dimethylpyridin-2-yl at the N-3 position of thiazolidin-4-one had a major impact on the anti-HIV-1 activity and was found to lower cytotoxicity. The substitution of the heteroaryl ring with bromo group and bicyclic heteroaryl ring at N-3 thiazolidin-4-one was found to lower anti-HIV-1 activity and increase cytotoxicity. The undertaken docking studies thus facilitated the identification of crucial interactions between the HIV-1 RT enzyme and thiazolidin-4-one inhibitors, which can be used to design new potential inhibitors.     

Synthesis and biological evaluation of some novel triazol-3-ones as antimicrobial agents

A new series of triazol-3-one derivatives bearing 4-methyl-4H-thieno[3',2': 5,6]thiopyrano[4,3-d][1,3]thiazolyl or 4-(thiophene-3-yl) thiazolyl moiety at 4-position and alkyl substitution at 2-position are synthesized. All the synthesized compounds are characterized by elemental analysis, IR, (1)H NMR, (13)C NMR, and mass spectral data. The newly synthesized compounds are screened for antifungal and antibacterial activities.     

Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular ‘click chemistry’ approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78 μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β-d-ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding interactions.     

Synthesis,biological evaluation and molecular docking studies of novel 3,5-disubstituted 2,4-thiazolidinediones derivatives

A series of thirteen novel 2,4-thiazolidinedione derivatives were synthesized through three step reaction procedure. The title compounds were synthesized by Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione ring. Various physicochemical and spectral studies were conducted to characterize the synthesized derivatives including- IR, Mass, ¹H NMR, ¹³C NMR and elemental analysis. The derivatives were screened for in vivo anti diabetic, in vivo anti-inflammatory and in vitro free radical scavenging activities by carrageenan induced rat paw edema method, alloxan induced diabetes in wistar rats method and FRAP (ferric reducing antioxidant power) method respectively. Some of the derivatives emerged out as potent antidiabetic, anti inflammatory and free radical scavenging agents. Molecular docking was carried out to investigate some possible structural insights into the potential binding patterns of the most potent anti-diabetic molecules NB7,NB12 and NB13 with the active sites of target PPARγ (PDB ID: 2PRG) using MOE software. Dichloro derivative compound NB-7 has shown great potential in the present study as it not only has maximum antidiabetic activity but also possess excellent anti-inflammatory and antioxidant potential.