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The rapid emergence of drug resistance severely reduces the clinical response of human immunodeficiency virus-1 (HIV-1) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, a series of 2,4,6-trisubstituted pyrimidine derivatives was designed and synthesized, with the aim to identify novel anti-HIV-1 agents with improved drug resistance profiles. The antiviral activity results demonstrated that all compounds showed excellent potency to wild-type (WT) HIV-1 strain (EC 50 = 3.61–15.5 nM). Moreover, 13c was proved to be the most potent inhibitor against the whole tested viral panel, with EC 50 ranging from 4.68 to 229 nM. In addition, 13c yielded moderate HIV-1 RT inhibition with IC 50 value of 0.231 μM, which demonstrated it was a classical NNRTI. Molecular docking was further conducted to illustrate its binding mode with HIV-1 RT. These encouraging results indicated that 13c can be used as a lead compound for further study. [Display omitted] • 24 novel 2,4,6-trisubstituted pyrimidine derivatives were designed through structure-based drug design. • 13c exhibited potent anti-HIV-1 activity against the whole tested viral panel with EC 50 ranging from 4.68 to 229 nM. • HIV-1 RT inhibition and molecular docking experiments validate the target of 13c , illustrating its binding mode with RT. [ABSTRACT FROM AUTHOR]

Ion channels are a type of protein channel that play a vital role in numerous physiological functions by facilitating the passage of ions through cell membranes, thereby enabling ion and electrical signal transmission. As a crucial target for drug action, ion channels have been implicated in various diseases. Many natural products from marine organisms, such as fungi, algae, sponges, and sea cucumber, etc. have been found to have activities related to ion channels for decades. These interesting natural product molecules undoubtedly bring good news for the treatment of neurological and cardiovascular diseases. In this review, 92 marine natural products and their synthetic derivatives with ion channel-related activities that were identified during the period 2000–2024 were systematically reviewed. The synthesis and mechanisms of action of selected compounds were also discussed, aiming to offer insights for the development of drugs targeting ion channels. [Display omitted] • As a crucial target for drug action, ion channels have been implicated in various diseases. • 92 marine natural products and their synthetic derivatives with ion channel-related activities during the period 2000–2024 were systematically reviewed. • Marine natural products and their synthetic analogues had a huge potentiality designed for drugs targeting ion channels. • Study on the effect of marine natural products about the non-conducting functions of ion channels should be strengthened. [ABSTRACT FROM AUTHOR]

Abstract Benzofuran is a fundamental structural unit in a variety of biologically active natural products, and its derivatives display various biological properties. Some benzofuran derivatives possess unique anti-tubercular and anti-bacterial action mechanism, and exhibit excellent in vitro and in vivo activities against both drug-sensitive and drug-resistant pathogens. Moreover, several benzofuran derivatives have already used in clinics for the treatment of various diseases. Thus, benzofuran is a useful pharmacophore to develop new anti-tubercular and anti-bacterial drugs. This review covers the recent advances of benzofuran derivatives as potential anti-tubercular and anti-bacterial agents, and the structure-activity relationship is also discussed to pave the way for the further rational development of this kind of derivatives. Graphical abstract Benzofuran derivatives possess a broad spectrum of chemotherapeutic properties, and some of benzofuran-based compounds have already used in clinics for the treatment of various diseases, so benzofuran derivatives occupy an important position in the development of new drugs. This review covers the recent advances of benzofuran derivatives as potential anti-tubercular and anti-bacterial agents. The structure-activity relationship is also discussed to pave the way for the further rational development of this kind of derivatives. Image 1 Highlights • Some benzofuran derivatives exhibited excellent in vitro and in vivo activities against both drug-sensitive and drug-resistant pathogens. • This review covers the recent advances of benzofuran derivatives as potential anti-TB and anti-bacterial agents. • The structure-activity relationship was discussed to pave the way for the further rational design. [ABSTRACT FROM AUTHOR]

Abstract Cancer is a leading cause of death generally, and to overcome this problem the introduction of a new drug developing is a continuous endeavour. An alkaloid, norharmane and its derivatives, which have anticancer activities, widely distributed in several living and synthetic chemical sources. Herewith, the suggested mechanisms of organic reactions and synthetic approaches of norharmane available so far were considered. Active sites of norharmane nucleus positions, C-1, C-3, and N-9, were used for developing new molecules and based on structure activity relationship (SAR), those have been seen with anticancer activities. This review summarizes on chemistry of synthetic strategies of norharmane derivatives, which may provide a framework to design a novel anticancer drug, in future. Graphical abstract Image 1 Highlights • The review emphasized on synthetic method approach of norharmane and its derivatives. • Anticancer activity of lead molecule from several prescribed schemes. • Elaborated on SAR of norharmane nucleus. [ABSTRACT FROM AUTHOR]

Abstract A series of novel pleuromutilin derivatives embracing 7 H -pyrrolo[2,3- d ]pyrimidine moiety were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative pathogens as well as in vivo efficacy in lethal systemic infected mice. Most compounds displayed good in vitro potency against MSSA, MRSA, MSSE, MRSE and E. faecium (MIC = 0.0625–4 μg/mL), especially 15a , 15b and 15o showed excellent activity that even more active than the comparator valnemulin. The in vivo efficacy investigation exhibited compound 15a (ED 50 = 16.0 mg/kg) had comparable activity to valnemulin (ED 50 = 13.5 mg/kg). The results provided by the dose-response study demonstrated 15a can supply infected mice with 70% survival rate at dose of 40 mg/kg via intragastric (i.g.) administration. Graphical abstract Image 1 Highlights • Fifteen novel peluromutilin derivatives linking 7 H -pyrrolo[2,3- d ]pyrimidine were synthesized. • Compounds 15a presented the best in vitro antibacterial activity. • The in vivo efficacy of compounds 15a was equal to valnemulin. • 15a might be a promising lead compound for new antibacterial agent. [ABSTRACT FROM AUTHOR]

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed. Graphical abstract Image 1 Highlights • Inhibition of PCSK9 with small molecules is a promising strategy to lower LDL-C. • This review provides an update of recent advances in small-molecule PCSK9 inhibitors. • Challenges and strategies to discover small-molecule PCSK9 inhibitors are discussed. [ABSTRACT FROM AUTHOR]

Abstract In an attempt to develop new antimalarial drugs, we have synthesized a new class of N -alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by dehydration. The newly synthesized compounds were screened for their in vitro antiplasmodial activity, and among all the compounds 9g , 9f , 9b , 8d , 9d , 9c , and 9e displayed potent activity with the IC 50 values in the range of 0.1–0.3 μM against Chloroquine (CQ) sensitive Pf 3D7 strain, while compounds 9d , 9b , 9e , 8c , 8f , 9c , and 9a have shown promising activity having IC 50 values in 0.1–0.4 μM range against CQ resistant Pf K1 strain, which is even better than the standard drug chloroquine with IC 50 value of 0.5 μM. Graphical abstract Image 1 Highlights • A series of glucoconjugated oxindoles were accessed from glucosyl propanone and isatin. • These compounds were accessed by simple cross-aldol reaction followed by dehydration. • 10 compounds showed potent activity with IC 50 in 0.11 – 0.77 μM against Pf 3D7 strain. • 10 compounds showed promising activity with IC 50 in 0.15 – 0.94 μM against Pf K1 strain. • Activity is enhanced in compounds having exocyclic double bond and 5-chloro substituent. [ABSTRACT FROM AUTHOR]

Abstract Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2. Graphical abstract Image 1 Highlights • Extension of mono to diaryl hydroxylamines illuminates activities as potent pan and dual inhibitors of IDO1, IDO2 and TDO. • There is a paucity of previous reports of dual and pan inhibitors for these enzymes, which regulate the kynurenine pathway. • Aryl halide substitution generated the most potent derivatives studied. [ABSTRACT FROM AUTHOR]

Abstract An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, h MAO-B IC 50 = 1.11 nM, K i = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, h MAO-B IC 50 = 3.27 nM, K i = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1 H -pyrrolo[3,2- b ]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model. Graphical abstract Image 1 Highlights • Selective and reversible MAO-B inhibitors have been developed. • (Pyrrolo-pyridin-5-yl)benzamides 10 , 14 – 16 show high BBB in vitro permeability. • Compound 15 exhibits also excellent water solubility. • Compound 14 showed a large neuroprotective effect on cortical neurons. • The neuroprotective effect of 14 observed also in a cell-based neurovascular unit model (+BBB). [ABSTRACT FROM AUTHOR]

Abstract T–lymphokine-activated killer cell–originated protein kinase (TOPK) is a serine-threonine mitogen-activated protein kinase that is highly expressed in many types of human cancer. Due to its important role in cancer progression, TOPK is becoming an attractive target in chemotherapeutic drug design. In this study, a series of 1-phenyl phenanthridin-6(5 H)-one derivatives have been identified as a novel chemical class of TOPK inhibitors. Some of them displayed very potent anti-cancer activity with IC 50 s less than 100 nM, superior than reference compound OTS964. The most potent compound, 9g suppressed the growth of cancer cells by apoptosis and specifically inhibited the activities of TOPK. Oral administration of 9g effectively suppressed tumor growth with TGI >79.7% in colorectal cancer xenograft models, demonstrating superior efficacy compared to OTS964. Pharmacokinetic studies reveal its good oral bioavailability. Our findings therefore show that 9g is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic agent against colorectal cancer. Graphical abstract Image 1 Highlights • 1-Phenyl Phenanthridin-6(5 H)-ones have been discovered as new TOPK inhibitors. • 9g markedly inhibited proliferation of colorectal cancer cell lines in vitro. • 9g suppressed tumor growth in vivo and exhibited good pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Abstract Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS-inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (K i) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1 , 5-10 , 5-22 , 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best K i of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target. Graphical abstract Image 1 Highlights • 68 novel ethoxysulfuron derivatives were synthesized in sodium salts. • 5-1 had the best K i of 6.7 nM against C. albicans acetohydroxyacid synthase. • 5-1 exhibited antifungal activity in both cell based assay and nematode model. • Molecular simulations were performed for the target compounds. [ABSTRACT FROM AUTHOR]

Abstract The transcription factor STAT3 is an attractive target for a variety of cancers therapy. Napabucasin, applied in phase III clinical trials for the treatment of a variety of cancers, was regarded as one of the most promising anticancer drug by targeting STAT3. Herein, a novel series of napabucasin derivatives were designed and synthesized, which presented a potent inhibitory activity on a variety of cancers cells. Among the derivatives compound 8q exhibited potent inhibitory activity on U251, HepG2, HT29 and CT26 cells with the IC 50 values of 0.22, 0.49, 0.07 and 0.14 μM, respectively, which was over 10-fold more potent than napabucasin. Treatment with compound 8q decreased protein expression level of total STAT3 and p-STAT3Y705 in vitro. The binding of compound 8q with STAT3 were further validated by electrophoretic mobility shift assay and surface plasmon resonance analysis. Compound 8q has a K D of 110.2 nM for full-length STAT3 recombinant protein. Moreover, the aqueous solubility of 8q was over 4.5-fold than that of napabucasin. In addition, compound 8q in vivo significantly reduced tumor growth compared to untreated mice, and exhibited good safety profile, indicating its great potential as an efficacious drug candidate for oncotherapy. Graphical abstract Image 1 Highlights • In vitro , compound 8q was over 10-fold more potent than napabucasin on U251, HepG2, HT29 and CT26 cells. • In mouse model of colorectal cancer, 8q significantly reduced tumor growth. The TGI of 8q at 50 mg/kg was 63%. • Compound 8q has a K D of 110.2 nM for full-length STAT3 recombinant protein by surface plasmon resonance analysis. • The aqueous solubility of 8q was over 4.5-fold higher than that of napabucasin. • Compound 8q exhibited good safety profile in BALB/c mice model. [ABSTRACT FROM AUTHOR]

A novel series of substituted N -aminothioglycolurils was synthesized by tandem hydrazone formation – ring contraction reaction of 3-thioxoperhydroimidazo[4,5- e ]-1,2,4-triazin-6-ones with ( E )-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S -Alkyl substituted N -aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S -methyl derivatives can be substituted with hydroxyl group in acid medium to give N -aminoglycolurils. Representative compounds were evaluated for their cytotoxic activity against RD, A549, HCT116 and MCF7 human cancer cell lines by MTT-assay and screened for their antifungal activity against phytopathogenic fungi using the mycelium growth inhibition method in vitro . Among the derivatives, 4-(( E )-(( E )-3-(2-Methoxyphenyl)allylidene)amino)-3-methyl-1-phenylthioglycoluril 8i was found to have the highest antiproliferative activity toward the RD and HCT116 cell lines ( 8i : IC 50 = 0.02 and 0.012 μM, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-(( E )-(( E )-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 8l showed the most marked activity toward A549 cells ( 8l : IC 50 = 0.61 μM) compared to reference drugs. The IC 50 values of thioglycolurils 8i,l against normal human embryonic kidney cells HEK293 were 0.23 and 86.11 μM, respectively, exceeding the IC 50 values of this compound toward the RD, HCT116 ( 8i ) and A549 cells ( 8l ) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,l induced apoptosis in Jurkat cells (acute T cell leukemia). Alkylthioderivatives 12a,13a displayed the strongest antifungal action against R. solani , F. oxysporum , and F. moniliforme exceeding those of triadimefon. [ABSTRACT FROM AUTHOR]

Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors. Most compounds showed potent LSD1 and HDACs inhibitory activity, especially compound 7 displayed the most potent inhibitory activity against HDAC1 and HDAC2 with IC 50 of 15 nM and 23 nM, as well as potent inhibition against LSD1 with IC 50 of 1.20 μM. Compound 7 demonstrated stronger anti-proliferative activities than SAHA with IC 50 values ranging from 0.81 to 4.28 μM against MGC-803, MCF-7, SW-620 and A-549 human cancer cell lines. Further mechanistic studies showed that compound 7 treatment in MGC-803 cells dose-dependently increased cellular H3K4 and H3K9 methylation, as well as H3 acetylation, decreased the mitochondrial membrane potential and induced remarkable apoptosis. Docking studies showed that compound 7 can be well docked into the active binding sites of LSD1 and HDAC2. This finding highlights the potential for the development of LSD1/HDACs dual inhibitors as novel anticancer drugs. [ABSTRACT FROM AUTHOR]

Phenotypic screening of high quality compound library is one of the most effective strategy to obtain novel bioactive compounds. Recently, our group have constructed a Wogonin-scaffold library with substituents diversity and successfully obtained a series of potent compounds. Herein, we reported the synthesis of these compounds and evaluated the in vitro antitumor activity against a panel of human tumor cell lines. Most of them showed good activity with a broad spectrum and preliminary structure-activity relationship for the substitutions were obtained. Further biological assays showed that the most potent compounds 18n and 20b could significantly enhance the intracellular ROS level and induce the cell apoptosis at low micromole level. Through similarity searching, CDK9 was identified as the potential target for 20b , which could be a start point for next structure-based drug design. [ABSTRACT FROM AUTHOR]

Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico -based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies. On the basis of these studies, six analogues of Lavendustine B, containing the benzylamino-hydroxybenzoic scaffold, were selected for synthesis and structure activity-relationship (SAR) studies. Our results demonstrated a good correlation between computational and experimental data, and all six analogues displayed an improved potency for inhibiting IN binding to LEDGF/p75 in vitro to respect to the parent compound Lavendustin B. Additionally, these analogs show to inhibit weakly LEDGF/p75-independent IN catalytic activity suggesting a multimodal allosteric mechanism of action. Nevertheless, for the synthesized compounds similar profiles for HIV-1 inhibition and cytoxicity were highlighted. Taken together, our studies elucidated the mode of action of Lavendustin B analogs and provided a path for their further development as a new promising class of HIV-1 integrase inhibitors. [ABSTRACT FROM AUTHOR]

Herein we report the synthesis of N -alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of β-glucosidase, K i = 1.6–5.5 μM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, K i up to 5.8 μM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H 2 O 2 ( K cat / K uncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe) 2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders. [ABSTRACT FROM AUTHOR]

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. Three series of tetracyclic oxindole derivatives were designed, synthesized and evaluated for α-glucosidase inhibitory activity in vitro . Compound 6t exhibited the most potent inhibitory activity with IC 50 0.7 μM and was about 170 times as active as acarbose (IC 50 = 115.8 μM). The kinetic analysis of compound 6t revealed it inhibited α-glucosidase in an irreversible and mixed manner. Fluorescence spectra indicated that 6t directly bound to α-glucosidase. Docking simulation showed the existence of potential H-bonding, van der Waals, Pi and Sigma-Pi interactions between 6t and α-glucosidase. [ABSTRACT FROM AUTHOR]

The ability of several N -phenyl-1 H -pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl- N -phenyl-1 H -pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC 50 ranging from 2.3 to 32 μM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva ( Galleria mellonella ) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections. [ABSTRACT FROM AUTHOR]

Ursolic acid (UA) is a pentacyclic triterpenoid with recognized anticancer properties. We prepared a series of new A-ring cleaved UA derivatives and evaluated their antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines using 2D and 3D culture models. Compound 17 , bearing a cleaved A-ring with a secondary amide at C 3, was found to be the most active compound, with potency in 2D systems. Importantly, even in 3D systems, the effect was maintained albeit a slight increase in the IC 50 . The molecular mechanism underlying the anticancer activity was further investigated. Compound 17 induced apoptosis via activation of caspase-8 and caspase-7 and via decrease of Bcl-2. Moreover, induction of autophagy was also detected with increased levels of Beclin-1 and LC3A/B-II and decreased levels of mTOR and p62. DNA synthetic capacity and cell cycle profiles were not affected by the drug, but total RNA synthesis was modestly but significantly decreased. Given its activity and mechanism of action, compound 17 might represent a potential candidate for further cancer research. [ABSTRACT FROM AUTHOR]

A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5–6 steps in 25–45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluated by MTT assay in vitro . SAR study suggested that the combination of 1-benzyl and 5-[ trans -2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhanced their cytotoxic activity. Among them, compound 2h was shown to have a significant cytotoxic activity with an IC50 value of 0.03 μM, more than 330-fold higher than that of it's mother molecule isatin. Investigation of the cell morphology changes and annexin-V/PI staining study demonstrated that compound 2h inhibited the proliferation of Jurkat cells by inducing apoptosis. Since compound 2h induced the dissipation of mitochondrial membrane potential and the activation of caspase-3, it was obvious that compound 2h inhibited the proliferation of Jurkat cells through the mitochondrial apoptotic pathway. Other than this, compound 2h exerted inhibition effect to many other tumor cells and only showed weak cytotoxic to human normal cells suggesting that compound 2h possessed a broad range of anticancer spectrum and high safety to normal cells. [ABSTRACT FROM AUTHOR]

We previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirteen of these derivative compounds inhibited HSV-2 replication by > 1000- to ∼100,000-fold at 1 μM and displayed EC 50 values lower than that of acyclovir, as well as low cytotoxicity, indicating their strong therapeutic potential. Through structural comparison, we also provide evidence for the importance of various structural motifs to the efficacy of ciclopirox and its derivatives, namely hydrophobic groups at R4 and R6 of the ciclopirox core structure. Like ciclopirox, representative analogs exhibit some oral bioavailability but are rapidly cleared in vivo. Together, these results will guide further development of N -hydroxypyridones as HSV therapeutics. [Display omitted] • Synthesis of analogs of ciclopirox. • Inhibition of HSV-2 replication by > 1000- to ∼100,000-fold at 1 μM. • Anti-HSV-2 EC 50 values lower than that of acyclovir. • Some analogs exhibit oral bioavailability but are rapidly cleared in vivo. [ABSTRACT FROM AUTHOR]

Abstract: In this study, a general approach for the multifunctionalization of magnetic nanoparticles (MNPs) with drugs (Doxorubicin and Gemcitabine) and targeting moieties (Nucant pseudopeptide) for controlled and selective release is described. The functionalization is achieved by the formation of disulfide bonds between MNPs and drugs derivatives synthesized in this work. Our strategy consists in the introduction of a pyridyldisulfide moiety to the drugs that react efficiently with sulfhydryl groups of pre-activated MNPs. This approach also allows the quantification of the covalently immobilized drug by measuring the amount of the 2-pyridinethione released during the process. The linkers developed here allow the release of drugs without any chemical modification. This process is triggered under highly reducing environment, such as that present inside the cells. Complete release of drugs is achieved within 5–8 h under intracellular conditions whereas negligible percentage of release is observed in extracellular conditions. We propose here a modular general approach for the functionalization of nanoparticles that can be used for different types of drugs and targeting agents. [Copyright &y& Elsevier]

Abstract: Platelets are anucleated blood cells that play an important role both in the pathogenesis of atherosclerosis and subsequent thrombosis. Dendrimers have attracted great interest in biomedical applications. However, their interactions with cell compounds and compartments are nonselective, thus causing cytotoxicity and hemotoxicity. We derivatized PAMAM G4 and G5 dendrimers to evaluate their interactions with serum metabolites, their effects on the viability of red blood cells, and their antithrombotic properties. PAMAM G4 and G5 derivatives showed better hemocompatibility than the PAMAM G4 and G5 dendrimers without any derivatization (NH2). PAMAM G4-Arginine-Tos and G4-Lysine-Cbz act as potent inhibitors of platelet aggregation induced by ADP. PAMAM G4-Arginine-Tos also showed inhibition of platelet aggregation induced by collagen, TRAP-6 and arachidonic acid. Moreover, G4-Arginine-Tos present inhibition of platelet secretion and thrombus formation under flow conditions. Based on our study, the PAMAM G4-Arginine-Tos derivative is hemocompatible and produces desirable antiplatelet and antithrombotic effects. Thus, this compound has potential applications as an antithrombotic drug or a drug delivery vehicle. [Copyright &y& Elsevier]

More studies are needed to develop new drugs for problems associated with drug resistance and unfavorable side effects. The natural flavonoid of quercetin revealed a wide range of biological activities by the modulation of various targets and signaling pathways. However, quercetin's low solubility and poor bioavailability have restricted its applicability; as a result, researchers have attempted to design and synthesize numerous novel quercetin derivatives using various methodologies in order to modify quercetin's constraints; the physico-chemical properties of quercetin's molecular scaffold make it appealing for drug development; low molecular mass and chemical groups are two of these characteristics. Therefore, the biological activities of quercetin derivatives, as well as the relationship between activity and chemical structure and their mechanism of action, were investigated. These quercetin-based molecules could be valuable in the creation and discovery of medications for a number of diseases. [Display omitted] • Quercetin is a favorable agent with a great deal of attention. • Quercetin derivatives possess broad-spectrum biological activities. • The Quercetin prodrug/hybrid can be modified Quercetin's constraints and improve its biological activities. • Evaluation of the most potent Quercetin-based compounds was conducted to design/develop various drugs. [ABSTRACT FROM AUTHOR]

Abstract: An unusual Dimroth rearrangement occurring in the reaction leading to annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core allowed the isolation of the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. By decorating the linear isomer with the same chains that improved the biological activity of the angular isomers, new annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines were designed and synthesized. They were selected by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited strong antiproliferative activity up to nanomolar concentration. In vivo screenings of the most active compound, the N-[2-(1H-imidazol-4-yl)ethyl]-4-(3-phenyl-10-oxo-4,10-dihydrobenzothieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidin-4-yl)butanamide, showed its low toxicity and high potency. [Copyright &y& Elsevier]

Abstract: A series of new sulphonamido-quinoxaline derivatives 3(a–p) have been prepared which are structurally similar to the High Throughput Screening (HTS) hit identified by Porter and collaborator. The newly synthesized compounds 3b, 3c, 3f, 3i, 3j, 3l, 3n and 3o were further evaluated in the National Cancer Institute for in vitro cytotoxicity assay among them compound 3l showed highest activity against Leukemia RPMI-8226 cell lines (GI50: 1.11 μM) as compared to other tested compounds. It is to be noted that compound 3l shows significant activity (GI50: 1.11 μM) compared to the High Throughput Screening (HTS) hit identified by Porter and collaborator (IC50 = 1.3 μM). Further docking study confirms the c-Met kinase inhibitory mechanism of the synthesized compounds. [Copyright &y& Elsevier]

Abstract: Thirty-eight new (4-(4-substituted-phenyl/2,4-disubstituted-phenyl)-thiazol-2-yl)hydrazine derivatives were synthesized in good yield and assayed for their in vitro anti-Candida activity, compared to topical and systemic antifungal drugs, against twenty-two clinical isolates of Candida spp. The concurrent presence of aliphatic chains or cycloaliphatic rings at N1-hydrazine and a 4-methyl/4-methoxyphenyl at C4 position of the thiazole nucleus exhibited an interesting anti-Candida inhibitory activity. Moreover, some of the most active compounds showed synergistic antifungal effects and lower cell toxicity when combined with clotrimazole. [Copyright &y& Elsevier]

Abstract: Obatoclax is a linear oligopyrrole compound which antagonizes the antiapoptotic effects of the Bcl-2 family. Herein we describe the synthesis of obatoclax derivatives by replacement of the pyrrole and indole ring of obatoclax with thiophene, furan and thiazolidinedione. The in vitro cytotoxicity of the newly synthesized compounds is evaluated against hepatocellular carcinoma cells. Pyrrole and indole substituents of obatoclax analogues exhibited potent inhibition of cell growth. Among the tested compounds, 5d and 5e were active at 6.3 and 13.2 μM against PLC5 cells. Further assays confirmed a correlation between cell death, and p-STAT3 inhibition and SHP-1 activation by these analogues. [Copyright &y& Elsevier]

Abstract: Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC50s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC50s around 0.5 μM–3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation. [Copyright &y& Elsevier]

Abstract: Previously, we demonstrated that the multiple kinase inhibitor sorafenib mediates the repression of phospho-STAT3 in hepatocellular carcinoma cells. In this study, we used this kinase-independent mechanism as a molecular basis to use sorafenib as scaffold to develop a novel class of SHP-1-activating agents. The proof of principle of this premise was provided by SC-1, which on replacement of N-methylpicolinamide by a phenylcyano group showed abolished kinase activity while retaining phospho-STAT3 repressive activity. Structural optimization of SC-1 led to compound 6, which repressed phospho-STAT3 through SHP-1 activation and inhibited PLC5 cell proliferation at sub-micromolar potency. In light of the pivotal role of phospho-STAT3 in promoting tumorigenesis and drug resistance, this novel SHP-1-activating agent may have therapeutic relevance in cancer therapy. [Copyright &y& Elsevier]

Abstract: 30 novel compounds have been synthesized from 25-hydroxyprotopanaxadiol (25-OH–PPD) and their in vitro anti-tumor activities were tested on three cancer cell lines and one normal cell line (IOSE144) by standard MTT assay. The results showed that compound 27 exhibited the best anti-tumor activity in the in vitro assays. Compounds 1, 2, 16, 17, 18, 27, 28 and 29 have better anti-tumor activities against MCF-7 and A549 cancer cell lines than 25–OH–PPD, together with low toxicity in the normal cell. The results may provide useful data for researching and developing new antitumor agents. [Copyright &y& Elsevier]

Abstract: A series of novel gemifloxacin (GMFX) derivatives containing a substituted benzyloxime moiety with remarkable improvement in lipophilicity were synthesized. The target compounds evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that most of the target compounds have considerable potency against all of the tested Gram-positive strains including MRSA and MRSE (MIC: <0.008–8 μg/mL), although they are generally less active than the references against the Gram-negative strains. In particular, compound 11l (MIC: <0.008–4 μg/mL) was found to be 8–2048 and 2–128 times more potent than levofloxacin (LVFX) and GMFX against the Gram-positive strains, respectively. Moreover, against MRSA clinical isolates, 11l (MIC90: 1 μg/mL) is 8-fold more active than GMFX, and 2-fold more active than GMFX and moxifloxacin against MRSE clinical isolates (MIC90: 4 μg/mL). [Copyright &y& Elsevier]

Abstract: A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action. [Copyright &y& Elsevier]

Abstract: In this paper, 38 millepachine derivatives have been designed, synthesized and evaluated for their in vitro and in vivo antiproliferative activity. Among these novel derivatives, 15 displayed more potent antiproliferative activity than millepachine against HepG2, K562, SK-OV-3, HCT116, HT29, and SW620 tumor cells (mean IC50 = 0.64 vs. 2.86 μM, respectively). Furthermore, 15 could effectively inhibit tubulin polymerization in HepG2 cells, and induce the HepG2 cell cycle arrest at the G2/M phase in a concentration-dependant manner. Further studies confirmed that 15 significantly suppressed the growth of tumor volume and exerted more potent anticancer potency than millepachine and anticancer drug cisplatin in A549 lung xenograft tumor model. [Copyright &y& Elsevier]

Abstract: New 17-picolyl and 17-picolinylidene androstane derivatives, 3–10, 15, 18, 19, 22 and 23, were synthesized starting from 17α-picolyl-androst-5-en-3β,17β-diol (1) and 17(Z)-picolinylidene-androst-5-en-3β-ol (2). Reaction of 1 with m-chloroperoxybenzoic acid gives 5α,6α-epoxy N-oxide derivative 3, or, with Jones reagent, 3,6-dione derivative 4; while 17α-picolyl-androst-5-en-3β,4α,17β-triol (5) or 3β,4β,17β-triol (6) derivatives are obtainable from 1 using SeO2 in dioxane. Base-catalyzed tosyl group elimination from 7 or 9 affords AB conjugated derivatives 8 and 10. Oppenauer oxidation of 1 and 2 yields 4-en-3-one derivatives 11 and 12, which, with H2O2 in 4 M NaOH, affords 4α,5α and 4β,5β-epoxides 13, 14, 16 and 17. New 4-methoxy-3-keto derivatives 15 and 18 were obtained from 13 and 14, or, with methanol in 4 M NaOH, from 16 and 17. Reduction of 11 with NaBH4 gives 22, which was then acetylated to obtain 23. All new derivatives were screened for antitumor activity against human breast adenocarcinoma ER+, MCF-7; human breast adenocarcinoma ER-, MDA-MB-231; prostate cancer AR-, PC-3; human cervix carcinoma, HeLa; and colon cancer, HT-29 cells; as well as one human non-tumor cell line, MRC-5. Compounds 3, 5, 6, 8, 10, 18, 19 and 22 exhibited significant antitumor activity against MDA-MB-231 breast cancer cells; while 5, 6 and 10 also showed strong cytotoxicity against HT-29. Only compound 19 exhibited significant activity against MCF-7 breast cancer cells. No compounds displayed cytotoxicity against non-tumor MRC-5 cells. [Copyright &y& Elsevier]

Abstract: Direct inhibition of coagulation factor Xa (FXa) carries significant promise for developing effective and safe anticoagulants. Although a large number of FXa inhibitors have been studied, each can be classified as either possessing a highly flexible or a rigid core scaffold. We reasoned that an intermediate level of flexibility will provide high selectivity for FXa considering that its active site is less constrained in comparison to thrombin and more constrained as compared to trypsin. We studied several core scaffolds including 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid for direct FXa inhibition. Using a genetic algorithm-based docking and scoring approach, a promising candidate 23 was identified, synthesized, and found to inhibit FXa with a K i of 28 μM. Optimization of derivative 23 resulted in the design of a potent dicarboxamide 47, which displayed a K i of 135 nM. Dicarboxamide 47 displayed at least 1852-fold selectivity for FXa inhibition over other coagulation enzymes and doubled PT and aPTT of human plasma at 17.1 μM and 20.2 μM, respectively, which are comparable to those of clinically relevant agents. Dicarboxamide 47 is expected to serve as an excellent lead for further anticoagulant discovery. [Copyright &y& Elsevier]

Abstract: Capecitabine, an oral prodrug of 5-FU was developed to improve the tumor selectivity and tolerability. To enhance the efficacy of capacitabine, a series of 5′-deoxy-5-fluorocytidine derivatives 5a–e were synthesized. In the present study, we investigated antitumor activity of 5′-deoxy-5-fluorocytidine derivatives both in vivo and in vitro methods. Title compounds were non-mutagenic to Salmonella typhimurium tester strain in Ames test. Compounds 5d and 5e are potent to inhibit the proliferation of NCI-69, PZ-HPV-7, MCF-7 and HeLa cells in MTT assay. In particular, 5d and 5e showed potent antitumor activities against L1210 leukemia cell line. Collectively, these findings suggest that 5d and 5e are more potent anti-cancer compounds than capecitabine. [Copyright &y& Elsevier]

Abstract: Two series of novel 2-(2-arylmethylene)hydrazinyl-4-aminoquinazoline derivatives were synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2 and SGC-7901 cancer cell lines in vitro. Most compounds displayed moderate to excellent activity, with IC50 values ranging from 0.015 to 4.09 μM against all tested cell lines, respectively. The most promising compound 9p (E)-2-(2-((1-(2,3-dichlorobenzyl)-1H-imidazol-2-yl)methylene)hydrazinyl)-N-(1-methylpiperidin-4-yl)quinazolin-4-amine with IC50 values of 0.031 μM, 0.015 μM, 0.53 μM and 0.58 μM, which was 4- to 224 times more active than references 10 and Iressa, had emerged as a lead for further structural modifications. [Copyright &y& Elsevier]

Abstract: In the present study on the development of new anticonvulsants, twenty three 1-(2-arylhydrazinecarboxamido)-2,2-dimethylcyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Three compounds 6g, 6m and 6w showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6m showed the MES-induced seizures with ED50 value of 9.8 mg/kg and TD50 value of 332.2 mg/kg after intraperitoneally injection to mice, which provided compound 6m with a protective index (TD50/ED50) of 33.9 in the MES test. [Copyright &y& Elsevier]

Abstract: We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N-acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop-2-en-1-one and (E)-3-hydroxy-N′-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2-naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action. [Copyright &y& Elsevier]

Abstract: Five series of (Z)-5-(4-(2-oxo-2-phenylethoxy)benzylidene)-2-thioxothiazolidin-4-one derivatives (I–V) were synthesized, characterized, and evaluated for their anti-bacterial activity. Most of the synthesized compounds showed potent inhibition against several Gram-positive bacteria (including multidrug-resistant clinical isolates) with MIC values in the range of 1–32 μg/mL. Compounds IIIi, Vb and Vc presented the most potent activity, showing four-fold more potency than norfloxacin (MIC = 8 μg/mL and 4 μg/mL) and 64-fold more activity than oxacillin (MIC > 64 μg/mL) against MRSA CCARM 3167 and 3506 strains with MIC values of 1 μg/mL, and 64-fold more potency than norfloxacin (MIC > 64 μg/mL) and comparable activity to oxacillin (MIC = 1 μg/mL) against the QRSA CCARM 3505 and 3519 strains. None of the compounds exhibited any activity against the Gram-negative bacteria Escherichia coli 1356 at 64 μg/mL. [Copyright &y& Elsevier]

Abstract: A series of formononetin nitrogen mustard derivatives were synthesized and evaluated in vitro for their cytotoxicity against five cancer cell lines (SH-SY5Y, HCT-116, DU-145, Hela and SGC-7901). The pharmacological results showed that many of the new derivatives displayed more potent cytotoxicity than alkeran. Furthermore, compounds 6d and 6n could induce cell cycle arrest at G2/M phase and cell apoptosis. [Copyright &y& Elsevier]

Abstract: 24 derivatives (5a–x) derived from natural pyranochalcones (I and II) were designed and evaluated for their inhibitory potency on the production of nitric oxide (NO) in LPS-stimulated RAW264.7 cells. Among them, four compounds (5b, 5d, 5f, and 5h) exhibited more potent inhibitory effects on iNOS activity and iNOS-mediated NO production than a positive control indomethacin. Furthermore, 5b could significantly suppress the progression of carrageenan-induced hind paw edema compared to indomethacin at a dosage of 10 mg/kg/day, and dose-dependently ameliorated the development of adjuvant-induced arthritis (AIA) validated by arthritic scores and H&E staining of joints. In addition, docking study confirmed that 5b was an iNOS inhibitor with binding to the active site of murine iNOS. [Copyright &y& Elsevier]

Abstract: Starting from commercial available natural product oridonin (1), a practical synthesis of ent-6,7-seco-oridonin derivatives (2, 3, 5, and 9) was accomplished and their biological activities were evaluated. The conversion of spirolactone-type diterpenoid to enmein-type was first completed. The results demonstrated that all synthesized ent-6,7-seco-oridonin derivatives could markedly inhibit the proliferation of cancer cells. Compared with Taxol, the most cytotoxic compound 5 has similar potency in A549 cell and slightly less cytotoxicity in Bel-7402 cell. Compound 5 was also more potent than parent compound oridonin in mice with MGC-803 gastric cancer in vivo. Then a series of novel 14-O-derivatives of 5 were further designed and synthesized, which showed better activity than 5 and similar activity as Taxol in vitro. The structure–activity relationships of oridonin derivatives were also discussed in the present investigations. [Copyright &y& Elsevier]

Abstract: We recently discovered that five- and pseudo-five-fused-ring derivatives in an imidazonaphthyridine series were promising hit compounds for the development of new DNA-intercalators. In this study, novel (dihydro)imidazo[1,6] and [1,7]naphthyridi(no)nes were prepared including pseudo-pentacycles. All the compounds synthesized were screened against four tumor cell lines. Compounds 3(b–d) showed significant in vitro cytotoxicity, and DNA intercalation properties were demonstrated at 25μM. Imidazonaphthyridinones exhibited no DNA binding affinity despite significant growth inhibition activity. Interestingly, when a pyridinone pharmacophore was linked to the imidazo[1,2-a]pyridine scaffold, the geometric orientation of the link had a strong impact on the growth inhibition activity. From these results we conclude that the moderate cytotoxicity observed for these compounds is independent of their DNA-binding and topoisomerase inhibition activities. [Copyright &y& Elsevier]

Abstract: Histone deacetylases inhibitors (HDACIs) have become an attractive class of anticancer agents. In order to find some novel potent HDACIs, we designed and synthesized a series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives. All compounds exhibited potent HDAC-inhibitory activity, and two of them had similar potency to TSA. The introduction of 2-amino-4-phenylthiazole or 9-methyleneoxy-fluorenyl group at the surface recognize domain of these HDACIs could greatly increase their HDAC-inhibitory activity. Molecular modeling studies indicated that coordination of the zinc ion by these inhibitors, and formation of hydrogen bond and hydrophobic interaction between inhibitors and HDACs were essential for the HDAC-inhibitory activities of these inhibitors. Asp181, Asp269, Leu276 and Tyr308 in the active site of HDAC2 gave favorable contributions for binding with all compounds. [Copyright &y& Elsevier]

Abstract: A new family of quinolinone derivatives has been synthesized and evaluated for their antikinetoplastid activities against Leishmania donovani and Trypanosoma brucei brucei. Results from these structure–activity relationship studies enabled identification of compounds 3a and 4g as the most active compounds against L. donovani promastigotes and amastigotes parasites (IC50 values in a range of 2–11 μM). Additionally, compound 3b has emerged from this study as the most active compound in the series against T. b. brucei with a MEC value of 12 μM. These three compounds are worth of further in vivo evaluation. [Copyright &y& Elsevier]

Abstract: Common feature based pharmacophore and structure-based docking approaches have been employed in the identification of novel anti-HCV candidates from our in-house database. A total of 31 hits identified in silico were screened in vitro assay. 20 Compounds demonstrated anti-HCV activities (EC50 <50μM), including two naturally occurring flavones apigenin (21) and luteolin (22) with low micromole EC50 values and three compounds (23, 24 and 25) of novel scaffolds with moderate potencies. In addition, pharmacophore refinement was also conducted based on the current knowledge of flavone-derived anti-HCV candidates and the results of combined in silico and in vitro assays. [Copyright &y& Elsevier]

Abstract: In an effort to develop effective antiamoebic agents, some hydrazones and azoles containing pyridyl moiety were synthesized and screened for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Among all the compounds, only five compounds (1, 3, 5, 9 and 11) were found to be better inhibitors of growth of E. histolytica than the reference drug metronidazole. The cytotoxic studies of these compounds on human breast cancer MCF-7 cell line revealed that all the compounds were low-cytotoxic in the concentration range of 2.5–250μM. [Copyright &y& Elsevier]