Discovery of JMJD7 inhibitors with the aid of virtual screening and bioactivity evaluation.

Jumonji-C (JmjC) domain-containing 7 (JMJD7), which is a 2-oxoglutarate (2OG)-dependent oxygenase, has been demonstrated to play an important role in the occurrence and development of a number of diseases, particularly cancer. Discovery of JMJD7 inhibitors is thus of great importance. Herein consensus docking/scoring strategy and bioactivity evaluation were used to identify JMJD7 inhibitors from various chemical databases. Seven active compounds were retrieved. The most potent compound, Cpd-3, showed an IC50 value of 6.62 µM against JMJD7. Further biophysical assays confirmed that Cpd-3 could efficiently bind to JMJD7 in vitro. Flexible docking was used to predict the binding mode of Cpd-3 with JMJD7. In a cellular assay, Cpd-3 displayed good inhibitory activity against cancer cell lines expressing a high level of JMJD7. As far as we know, Cpd-3 is the first JMJD7 inhibitor reported so far. Overall, this study established a good starting point for drug discovery targeting JMJD7.

Synthesis, molecular structure, FT-IR and XRD investigations of 2-(4-chlorophenyl)-2-oxoethyl 2-chlorobenzoate: a comparative DFT study.

2-(4-Chlorophenyl)-2-oxoethyl 2-chlorobenzoate has been synthesized, its structural and vibrational properties have been reported using FT-IR and single-crystal X-ray diffraction (XRD) studies. The conformational analysis, optimized geometric parameters, normal mode frequencies and corresponding vibrational assignments of the synthesized compound (C15H10Cl2O3) have been examined by means of Becke-3-Lee-Yang-Parr (B3LYP) density functional theory (DFT) method together with 6-31++G(d,p) basis set. Furthermore, reliable conformational investigation and vibrational assignments have been made by the potential energy surface (PES) and potential energy distribution (PED) analyses, respectively. Calculations are performed with two possible conformations. The title compound crystallizes in orthorhombic space group Pbca with the unit cell dimensions a=12.312(5) Å, b=8.103(3) Å, c=27.565(11) Å, V=2750.0(19) Å(3). B3LYP method provides satisfactory evidence for the prediction of vibrational wavenumbers and structural parameters.

Synthesis, antimicrobial evaluation and QSAR studies of 2-chlorobenzoic acid derivatives.

In the present study, 2-chlorobenzoic acid derivatives were synthesized and evaluated for their antimicrobial activity against Gram-positive bacteria: Staphylococcus aureus, Bascillus subtilis, Gram-negative bacterium Escherichia coli, fungal strains: Candida albicans and Aspergillus niger by tube dilution method. Results of antimicrobial screening indicated that the synthesized compounds exhibited greater antibacterial potential against Gram-negative bacterium (Escherichia coli) than Gram-positive bacteria and the Schiff's bases of 2-chloro benzoic acid were more potent antimicrobial agents than its esters. Compound 6 (pMIC(am)=1.91 µM/ml, pMIC(ec)=2.27 µM/ml) emerged as most potent antimicrobial agent and was found comparable to standard drug norfloxacin (pMIC(ec)=2.61 µM/ml) against Escherichia coli. QSAR studies revealed that the antibacterial, antifungal and the overall antimicrobial activities of the 2-chlorobenzoic acid derivatives were governed by the topological parameters, second order and valence second order molecular connectivity indices ((2)χ and (2)χ(v)).

Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats.

The modification of 3'-((2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yloxy)methyl)biphenyl-4-carboxylic acid (BINA, 1) by incorporating heteroatoms into the structure and replacing the cyclopentyl moiety led to the development of new mGluR2 positive allosteric modulators (PAMs) with optimized potency and superior druglike properties. These analogues are more potent than 1 in vitro and are highly selective for mGluR2 vs other mGluR subtypes. They have significantly improved pharmacokinetic (PK) properties, with excellent oral bioavailability and brain penetration. The benzisothiazol-3-one derivative 14 decreased cocaine self-administration in rats, providing proof-of-concept for the use of mGluR2 PAMs for the treatment of cocaine dependence.

Efficient synthesis of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]-acetic acid, a novel COX-2 inhibitor.

The synthesis of 6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid (1), a selective cyclooxygenase 2 (COX-2) inhibitor, is described. The synthesis relied on a novel indole formation that involved an alkylation/1,4-addition/elimination/isomerization cascade. It was demonstrated that the entire sequence from sulfonamide 13 and bromoketone 14 to the desired indole (1) could be executed in a single pot.

Orally bioavailable benzisothiazolone inhibitors of human leukocyte elastase.

Human leukocyte elastase (HLE) has been proposed as a primary mediator of pulmonary emphysema and other inflammatory airway diseases. HLE is capable of cleaving many proteins, including elastin, other components of connective tissue, certain complement proteins, and receptors. Under normal conditions an appropriate balance exists in the lung between HLE and endogenous inhibitors, which scavenge the released enzyme before it exerts deleterious effects in the lung. Emphysema is thought to result from an imbalance in the lung between HLE and endogenous inhibitor (elevated elastase or insufficient inhibitor) that leads to the destruction of alveoli. We have identified WIN 64733 (2) and WIN 63759 (3) as potent (Ki* = 14 and 13 pM, respectively), selective, mechanism-based inhibitors of HLE which are orally bioavailable in the dog (absolute bioavailability 46% and 21%, respectively). In this series the in vitro stabilities of the inhibitors in blood, jejunal homogenates, and liver S9 homogenates are useful predictors of oral bioavailability. After being administered orally (30 mg/kg) to dogs, compounds 2 and 3 are found in the lung, being detected in the epithelial lining fluid obtained by bronchoalveolar lavage (Cmax of 2.5 and 0.47 microgram/mL, respectively).

Formation of a perbenzoic acid derivative in the photodegradation of fenofibrate: phototoxicity studies on erythrocytes.

The phototoxic antihyperlipoproteinemic drug fenofibrate (1) is photolabile under aerobic conditions. Irradiation of a methanol solution of 1 produces, under oxygen, photoproducts 2, 3, and 4. A peroxidic photoproduct 2 was isolated and identified. The biologically active antioxidants glutathione and cysteine efficiently reduce 2 to its acid. This photoproduct was also capable of efficiently oxidizing tetramethyl phenylendiamine (TMP) through an electron transfer mechanism, detecting a TMP+ species by UV-visible spectrometry. Fenofibrate was screened in vitro at different concentrations for UV-visible-induced phototoxic effects in a photohemolysis test, under oxygen as well as argon. The photohemolysis rate was low under anaerobic conditions. No hemolysis occurred without irradiation. The isolated photoproduct 2 induced hemolysis without irradiation.

Studies on the derivatives of aziridine. II. Synthesis and immunopharmacological analysis of substituted amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid.

Several new amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid were synthetized. The beta-/p-chlorobenzoyl/-acrylic acid 2 was used as the substrate. This compound was converted by reaction with appropriate amine into amides and anilides of beta-/p-chlorobenzoyl/-acrylic acid (3-10). These compounds react with ethylenoimine giving appropriate amides and anilides of alpha-aziridinyl-beta-/p-chlorobenzoyl/-propionic acid (11-18). When pharmacologically analyzed, they appeared to possess marked immunotropic activity. The derivatives in question modulated both humoral as well as cellular immune response, the effect being related to the type of substitutent in the amide group.

Studies on the derivatives of aziridine. I. synthesis and immunopharmacological analysis of amides of alpha-aziridinyl- beta-/p-chlorobenzoyl/-propionic acid.

Several new aziridinyl derivatives of beta-/p-chlorobenzoyl/propionic acid were synthesized (3, 5, 7, 14-18). The gamma-/p-chlorophenyl/-dihydrofuran-2-one 2 and beta-/p-chlorobenzoyl/acrylic acid 4 were used as the substrates. Compound 2 reacts with ethylenimine yielding aziridinylamide of beta-/p-chlorobenzoyl/-propionic acid 3. The sodium salt of acid 4 and methyl ester 6 were converted by reactions with ethylenimine into appropriate alpha-aziridinyl derivatives 5 and 7. The acid 4 in the reaction with phosphorus pentachloride gives the acid chloride 8 which is transformed under the influence of appropriate amines into corresponding amides 9-13. These amides react with ethylenimine giving the appropriate alpha-aziridinyl derivatives of beta-/p-chlorobenzoyl/-propionic acid 14-18. Pharmacological analysis revealed that the compounds studied possessed immunotropic activity; they modulate both humoral as well as cellular immune response. Their effect has been shown to be related to chemical structure and to substituents of the carboxyl group in particular.

[Asymmetric N,N-dialkyl-3,5-dichlorobenzamides having phytotoxic activity]. / N,N-Dialchil-3,5-diclorobenzamidi asimmetriche ad attività fitotossica.

Asymmetric N,N-dialkyl-3,5-dichlorobenzamides bearing on the amide N a sec.butyl group or a 1-methylbutyl or 1-ethylpropyl and a second C3 or C4 alkyl group which may be branched or linear, saturated or unsaturated, were prepared and tested for phytotoxicity in pre- and post-emergence experiments. As reference compounds were prepared and tested 3,5-dichlorobenzamides, isomers of the first series, characterized by the presence on the amide N of a n.butyl or ter.butyl in place of the sec.butyl, of a 1-ethylpropyl or other branched alkyl in place of the 1-methylbutyl and a second alkyl group (C2 leads to C4) of varying weight and nature. The results show that all the 3,5-dichlorobenzamides studied have high phytotoxic activity and good selectivity in respect of the two graminaceous weeds tested. The amides proving most active against the weeds were tested against some species of agricultural interest. The substances proving active against the weeds and atoxic for the agrarian species were characterized by the presence on the amide N of a branched C4 or C5 group and a second C3 or C4 group.

[Asymmetric chlorobenzoic acid N,N-dialkylamides having phytotoxic activity]. / N,N-Dialchilamidi asimmetriche dell'acido 3-clorobenzoico, ad attività fitotossica.

In continuation of research on phytotoxic substances with selective activity, pre- and post-emergence tests against some weed species were made using a series of 3-chlorobenzamides substituted on the amide nitrogen with a sec.butyl or a 1-methylbutyl group, the second alkyl substituent being linear, branched, saturated or unsaturated. Asymmetric 3-chlorobenzamides with a tert.butyl in place of sec.butyl or with an 1-ethylpropyl in place of 1-methylbutyl and with a second alkyl residue of different nature and with variable weight, were prepared and tested for the purposes of comparison. The results show that amides with excellent phytotoxicity and selectivity of action are obtained if a sec.butyl, 1-methylbutyl or 1-ethylpropyl group is retained and the second substituent on the amide nitrogen is suitably varied. The results give further information on the importance of the steric characteristics of the substituents on nitrogen in the phytotoxic N,N-dialkylamides.

[2-amino-3,5-dichloro-benzoic acid and 3-amino-2,5-dichloro-benzoic acid derivatives with phytotoxic action]. / Derivati degli acidi 2-amino-3,5-dicloro- e 3-amino-2,5-diclorobenzoici ad attività fitotossica.

Derivatives of 2-amino-3,5-dichloro- and 3-amino-2,5-dichlorobenzoic acids have been prepared in order to extend previous research regarding the phytotoxicity of these two acids and of the corresponding N,N-di,sec.butylamides. The methyl esters of the two acids, the corresponding acids acetylated on the amino group and their respective methyl esters, and the N,N-di,sec.butylamides acetylated or formylated on the amino group were prepared. All these compounds were subjected to pre- and post-emergence tests using seven representative weeds, using doses of 6 kg/ha and, where substances proved active, at lower doses also. The results showed the importance of the N,N-di,sec.butylamide of 2-amino-3,5-dichlorobenzoic acid which, in contrast to the other derivatives tested, shows selective activity. For 3-amino-2,5-dichlorobenzoic acids and the amides tested, it was confirmed that only the acid shows marked generic phytotoxic activity in both pre- and post-emergence tests. It should be noted that the methyl ester of 3-acetylamino-2,5-dichlorobenzoic acid shows selective phytotoxicity activity.