A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.

A series of benzylidene hydrazides (1-20) was synthesized and tested, in vitro, for antibacterial, antifungal and antiviral activities. The microbial screening results indicated that compounds having chloro and nitro substituents were the most active ones. The antiviral evaluation depicted that compounds 9 and 19 were active against Vesicular stomatitis virus (VSV) in HeLa cell cultures. QSAR investigations indicated that the multi-target QSAR model was effective in describing the antimicrobial (antibacterial and antifungal) activity over the one-target QSAR models. Further the mt-QSAR model indicated that the topological parameters, second order molecular connectivity index ((2)chi) and third order Kier's alpha shape index (kappaalpha(3)) are effective in describing the antimicrobial activity of synthesized hydrazides.

A new family of cyclic carbamate-estradiol derivatives has been designed to remove the intrinsic estrogenic activity of a parent acyclic compound reported as a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). The synthesis of two series of fused 16β,17β-oxazinone-estradiol derivatives, saturated compounds 7a-d and unsaturated compounds 10a-d, led to the identification of 10b, a 17β-HSD1 inhibitor (IC50 = 1.4 μM) without estrogenic activity in estrogen-sensitive T-47D cells. Interestingly, this compound was found selective over 17β-HSD2 and 17β-HSD12. A computational analysis of inhibitors into 17β-HSD1 by molecular docking also revealed interesting structure-activity relationships that could be helpful in the design of new generation of 16β,17β-oxazinone-estradiol analogs.

A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 μM). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.

Premature stop codons are the result of nonsense mutations occurring within the coding sequence of a gene. These mutations lead to the synthesis of a truncated protein and are responsible for several genetic diseases. A potential pharmacological approach to treat these diseases is to promote the translational readthrough of premature stop codons by small molecules aiming to restore the full-length protein. The compound PTC124 (Ataluren) was reported to promote the readthrough of the premature UGA stop codon, although its activity was questioned. The potential interaction of PTC124 with mutated mRNA was recently suggested by molecular dynamics (MD) studies highlighting the importance of H-bonding and stacking π-π interactions. To improve the readthrough activity we changed the fluorine number and position in the PTC124 fluoroaryl moiety. The readthrough ability of these PTC124 derivatives was tested in human cells harboring reporter plasmids with premature stop codons in H2BGFP and FLuc genes as well as in cystic fibrosis (CF) IB3.1 cells with a nonsense mutation. Maintaining low toxicity, three of these molecules showed higher efficacy than PTC124 in the readthrough of the UGA premature stop codon and in recovering the expression of the CFTR protein in IB3.1 cells from cystic fibrosis patient. Molecular dynamics simulations performed with mutated CFTR mRNA fragments and active or inactive derivatives are in agreement with the suggested interaction of PTC124 with mRNA.

The HIV-1 protease has proven to be a crucial component of the HIV replication machinery and a reliable target for anti-HIV drug discovery. In this study, we applied an optimized hierarchical multistage virtual screening method targeting HIV-1 protease. The method sequentially applied SVM (Support Vector Machine), shape similarity, pharmacophore modeling and molecular docking. Using a validation set (270 positives, 155,996 negatives), the multistage virtual screening method showed a high hit rate and high enrichment factor of 80.47% and 465.75, respectively. Furthermore, this approach was applied to screen the National Cancer Institute database (NCI), which contains 260,000 molecules. From the final hit list, 6 molecules were selected for further testing in an in vitro HIV-1 protease inhibitory assay, and 2 molecules (NSC111887 and NSC121217) showed inhibitory potency against HIV-1 protease, with IC50 values of 62 μM and 162 μM, respectively. With further chemical development, these 2 molecules could potentially serve as HIV-1 protease inhibitors.

The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups.

A series of 3-(4-(aminoalkoxy)benzylidene)-chroman-4-ones 7a-r were designed and synthesized as analogs of homoisoflavonoids which are well known natural products with diverse pharmacological properties related to Alzheimer's disease. The in vitro anti-cholinesterase activity of designed compounds 7a-r against AChE and BuChE, revealed that compounds bearing piperidinylethoxy residue showed potent activity against AChE at sub-micromolar level (IC50 values = 0.122-0.207 μM), more potent than reference drug tacrine. The structure-activity relationships study of piperidinylethoxy series demonstrated that the selectivity and physicochemical properties of compounds could be optimized by selection of a proper substituent on the C-7 position of chroman ring, while the high potency of the molecule against AChE was reserved.

Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.

A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, (1)H NMR, (13)C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability.

Trypanosomatids are protozoan parasites that cause various diseases in human, such as leishmaniasis, Chagas disease and sleeping sickness. The highly syntenic genomes of the trypanosomatid species lead the assumption that they can encode similar proteins, indicating the possibility to design new antitrypanosomatid drugs with dual trypanosomicidal and leishmanicidal activities. In this work a series of compounds (6a-h and 7a-h), containing a semicarbazone scaffold as a peptide mimetic framework, was designed and synthesized. From this series compound 7g (LASSBio-1483) highlighted, showing dual in vitro trypanosomicidal and leishmanicidal activities, with potency similar to the standard drugs nifurtimox and pentamidine. This data, taken together with its good in silico druglikeness profile and its great chemical and plasma stability, make LASSBio-1483 (7g) a new antitrypanosomatid lead-candidate.

Three transition metal complexes with isoquinoline derivatives: [(MPDQ)2Zn(C2H5OH)ClO4]ClO4 (1) (MPDQ = 4,5-methylenedioxy-1-pyridinedihydroisoquinoline), [(PYP)2Zn(H2O)](ClO4)2 (2) (PYP = 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline) and [(MPDQ)2Ni(CH3OH)ClO4]ClO4 (3) were synthesized and fully characterized. All complexes exhibited strong proliferation inhibition activity against various tested cancer cells with high selectivity to tumour and normal cells. BEL-7404 cells were found most sensitive to complex 2 by inducing apoptosis. The process involved the mitochondrial membrane potential depolarization, PARP-proteins cleavage, Bcl-2, p53, p21 expression and caspase family members' activation. Taking these findings into account, it can propose that complex 2 induce cancer cell apoptosis via mitochondrial pathways. The interaction of complex 2 with DNA investigated by fluorescence, CD and viscosity indicated that complex 2 interact with DNA mainly via intercalation.

A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3'-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease.

Herein, we describe the synthesis, biological evaluation and molecular docking of the selective PPARβ/δ antagonist (4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl)ethyl)thiazole-5-carboxamide)), CC618. Results from in vitro luciferase reporter gene assays against the three known human PPAR subtypes revealed that CC618 selectively antagonizes agonist-induced PPARβ/δ activity with an IC50 = 10.0 μM. As observed by LC-MS/MS analysis of tryptic digests, the treatment of PPARβ/δ with CC618 leads to a covalent modification of Cys249, located centrally in the PPARβ/δ ligand binding pocket, corresponding to the conversion of its thiol moiety to a 5-trifluoromethyl-2-pyridylthioether. Finally, molecular docking is employed to shed light on the mode of action of the antagonist and its structural consequences for the PPARβ/δ ligand binding pocket.

Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT.

Despite the close structural similarity between the heptapeptide cores of the glycopeptide antibiotics teicoplanin and ristocetin, synthetically modified derivatives of their aglycons show significantly different antibacterial and antiviral properties. The teicoplanin aglycon derivatives with one exception proved to be potent antibacterials but they did not exhibit anti-influenza virus activity. In contrast, the aglycoristocetin derivatives generally showed high anti-influenza virus activity and possessed moderate antibacterial activity. A systematic structure-activity relationship study has been carried out on ristocetin and teicoplanin aglycon derivatives, to explore which structural differences are responsible for these markedly different biological activities. According to electronic circular dichroism and in silico conformational studies, it was found that the differences in anti-influenza virus activity are mainly determined by the conformation of the heptapeptide core of the antibiotics controlled by the presence or absence of chloro substituents. Knowledge of the bioactive conformation will help to design new analogs with improved anti-influenza virus activity. For the teicoplanin derivatives, it was shown that derivatization to improve the antiviral efficacy was accompanied by a significant decrease in antibacterial activity.

1H-1,2,3-triazole tethered isatin-ferrocene conjugates were synthesized and evaluated for their antiplasmodial activities against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The conjugates 5f and 5h with an optimum combination of electron-withdrawing halogen substituent at C-5 position of isatin ring and a propyl chain, introduced as linker, proved to be most potent and non-cytotoxic among the series with IC50 values of 3.76 and 4.58 μM against 3D7 and W2 strains, respectively.

In this paper, the design, synthesis and biological evaluation of a set of quinazoline-2,4,6-triamine derivatives (1-9) as trypanocidal, antileishmanial and antiplasmodial agents are explained. The compounds were rationalized basing on docking studies of the dihydrofolate reductase (DHFR from Trypanosoma cruzi, Leishmania major and Plasmodium vivax) and pteridin reductase (PTR from T. cruzi and L. major) structures. All compounds were in vitro screened against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promatigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain), and also for cytotoxicity using Vero cell line. Against T. cruzi, three compounds (5, 6 and 8) were the most effective showing a better activity profile than nifurtimox and benznidazole (reference drugs). Against L. mexicana, four compounds (5, 6, 8, and 9) exhibited the highest activity, even than glucantime (reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo Plasmodium berghei assay (ANKA strain), the compounds 1, 5, 6 and 8 showed a more comparable activity than chloroquine and pyrimethamine (reference drugs) when they were administrated by the oral route. The antiprotozoal activity of these substances, endowed with redox properties, represented a good starting point for a medicinal chemistry program aiming for chemotherapy of Chagas' disease, leishmaniosis and malaria.

It is generally known that proliferation of human breast cancer cells is stimulated by excess estrogen namely 17β-estradiol. Therefore, reduction of 17β-estradiol production by inhibiting 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an interesting route for breast cancer treatment particularly during adjuvant therapy. This study investigated the structure-activity relationship of 17β-HSD1 inhibitors as to gain insights and understanding on the origins of 17β-HSD1 inhibitory activities. To meet this goal, multiple linear regression model was constructed and correspondingly the results revealed good predictivity (N = 31, R(2) = 0.9438, Q(2) = 0.8530). The model suggested that low molecular weight and energy were preferred as 17β-HSD1 inhibitors. Additionally, high molecular flexibility and high number of hydrogen bond donors were also shown to be important that is in correspondence to previously reported pharmacophore model of 17β-HSD1 inhibitors. Furthermore, molecular docking of inhibitors to 17β-HSD1 followed by anchor analysis suggested that three different pockets comprising of hydrogen bonding sites 1 and 2 as well as van der Waals contacts contributed to protein-ligand interactions. Post-docking analysis of potent compound 9 with 17β-HSD1 suggested that the binding modality was similar to the binding of substrate (i.e. estradiol) and its analog (i.e. equilin). Such information is useful in guiding the further design of novel and robust 17β-HSD1 inhibitors.

Two-dimensional bond-based bilinear indices and linear discriminant analysis are used in this report to perform a quantitative structure-activity relationship study to identify new trypanosomicidal compounds. A data set of 440 organic chemicals, 143 with antitrypanosomal activity and 297 having other clinical uses, is used to develop the theoretical models. Two discriminant models, computed using bond-based bilinear indices, are developed and both show accuracies higher than 86% for training and test sets. The stochastic model correctly indentifies nine out of eleven compounds of a set of organic chemicals obtained from our synthetic collaborators. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Both models show a good agreement between theoretical predictions and experimental results. Three compounds showed IC50 values for epimastigote elimination (AE) lower than 50 μM, while for the benznidazole the IC50 = 54.7 μM which was used as reference compound. The value of IC50 for cytotoxicity of these compounds is at least 5 times greater than their value of IC50 for AE. Finally, we can say that, the present algorithm constitutes a step forward in the search for efficient ways of discovering new antitrypanosomal compounds.