Publications

Human immunodeficiency virus type-1 (HIV-1) resistance severely compromises the efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs). This study developed novel DAPY-derived NNRTIs via a structure-based drug design strategy with <b>K-5a2</b> as the lead. All designed compounds demonstrate potent antiviral activity against the HIV-1 wild-type (WT) strain (EC₅₀ = 3.03-21.1 nM). Notably, compound <b>19</b> was identified as the most potent inhibitor against a panel of clinically relevant mutant strains (EC₅₀ = 5.03-37.7 nM) with resistance fold (RF) values (RF = 0.746-5.59) superior to that of ETR (RF = 1.11-15.5). Mechanistic studies confirmed that <b>19</b> potently inhibits HIV-1 RT (IC₅₀ = 0.107 μM). Molecular docking and MM/GBSA calculations validate its stable binding with NNIBP, mediated by extensive hydrogen bond networks, hydrophobic interactions, and π-π stacking. Collectively, this work delivers <b>19</b> as a highly promising next-generation NNRTI lead compound with exceptional resilience against drug-resistant HIV-1.

The prototype compounds of three different classes of nucleoside phosphonates [i.e. 9-(2-phosphonomethoxyethyl)adenine (PMEA), 9-(2-phosphonomethoxyethoxy)adenine (PMEoA) and 9-[(2R,5R)-2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]adenine (D4API)] were investigated and compared for their antiviral activities. The three test compounds showed a marked inhibition of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in CEW and MT-4 cell cultures [50% effective concentration (EC 50 ): 0.8-14μm]. D4API was 2- and 15-fold more inhibitory than PMEA and PMEoA, respectively. In contrast, the activity of PMEA against human hepatitis B virus (HHBV) in human hepatoma Hep G2 2.2.15 cells was 5- and 10-fold more pronounced than the activities of PMEoA and D4API, respectively (EC 50 1.2μm versus 10 and 6 μm, respectively). The inhibitory activity of D4API against Moloney murine sarcoma virus (MSV)-induced C3H/3T3 cell transformation was superior to the activities of PMEA and PMEoA by at least one order of magnitude (EC 50 for D4API 1.3μM, versus 2.8 and 14 μM for PMEA and PMEoA, respectively). The markedly greater inhibitory effect of D4API on MSV in vitro was in agreement with our In vivo findings that D4API inhibited MSV-induced tumour formation in newborn mice and delayed the MSV-associated animal death at a lower dose than PMEA or PMEoA. Both PMEA and D4API emerged as promising compounds that warrant further investigation for their anti-retrovirus and anti-hepadnavirus activities in vivo.

New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of alpha,alpha'-azobis(isobutyronitrile). All these polyanions, bearing 18-48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1-2.9 microM, while not being toxic to the host cells at concentrations up to 62 microM. These compounds were also active against a clinical HIV-1 isolate (HE) at >/=4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1-10 microM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.

Eight new carbocyclic nucleosides were prepared by mounting a purine (compounds 8-10), 8-azapurine (12 and 13) or pyrimidine (15, 16 and 17b) on the amino group of (1S,3R)-3-aminomethyl-2,2,3-trimethylcyclopentylmethanol (6). All the compounds were evaluated as antiviral and antitumor agents in a variety of assay systems. Only compound 8 showed any cytostatic activity against the tumor cell lines examined.

Extrusion based 3D printing is a popular additive manufacturing process for the production of plastic prototypes and single- or small series of functional products. The most common known extrusion based technique is Fused Deposition Modeling® , based on filament deposition. Although this is a popular 3D printing technique, there are some disadvantages which imposes some limitations for the end-users. Primarily the limited range of commercially available materials. Secondly the feed material needs to be a filament. In addition the diameter of the filament needs to be produced with a narrow tolerance with respect to the nozzle diameter, in order to prevent blocking of the nozzle. Especially the limited range of materials discourages a lot of end users to produce parts by means of extrusion based 3D printing. This resulted in the development of an alternative extrusion based additive manufacturing process. A good processing technique was found in the conventional plastic extrusion process in which granulate is fed into a plastic processing screw. The paper describes the comparing research between the extrusion based processes such as filament, syringe and screw extrusion, resulting in the choice for the screw extrusion based process. A concept for this process has been worked out and a functional screw extrusion based additive manufacturing process has been developed that complies with the objectives.

The syntheses of a series of 1-aryl-5-diethylamino-1-penten-3-one hydrochlorides 1 and 1-aryl-3-diethylamino-1-propanone hydrochlorides 4 were accomplished. Attempts to prepare the corresponding bis(5-aryl-3-oxo-4-pentenyl)ethylamine hydrochlorides 2 and bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 5 led to the formation of a series of 4-(beta-arylvinyl)-3-(beta-arylvinylketo)-1-ethyl-4-piperidi nol hydrochlorides 9 and 4-aryl-3-arylketo-1-ethyl-4-piperidinol hydrochlorides 11, most of which were converted subsequently into the corresponding quaternary ammonium salts 10 and 12, respectively. The structures of these compounds were determined by 1H NMR spectroscopy and confirmed by X-ray crystallography of representative molecules. Most compounds displayed significant cytotoxicity toward murine P388 and L1210 cells as well as human tumors. In general, Mannich bases containing olefinic bonds were more cytotoxic than the analogues without this functional group, while the piperidines 9 and 11 were more potent than the acyclic analogues 1 and 4, respectively. Correlations were noted between various physicochemical constants in the aryl rings and cytotoxicity. Compound 9d displayed promising in vivo activity against colon cancers. This study has revealed that the piperidines 9 and 11 constitute new classses of cytotoxic agents.