Mohammed M. Abadleh

HETEROCYCLES (H)-FUSED TO 4-OXOQUINOLINE-3-CARBOXYLIC ACID. PART IX. 1 SYNTHESIS OF 2,6-DIOXOTETRAHYDRO-1H- PYRROLO(3,2-H)QUINOLINE-7-CARBOXYLIC ACID

Interaction of deprotonated malonic esters with 7-chloro-8-nitro-4- oxoquinoline-3-carboxylate (1) gave the respective 7-(bis(alkoxycarbonyl)- methyl) derivatives (2, 3) which were converted into the corresponding 7-(carboxymethyl)-8-nitro-4-oxoquinoline-3-carboxylic acid (4). Reductive lactamization of the latter furnished the target tetrahydro-2,6-dioxo-1H-pyrrolo- (3,2-h)quinoline-7-carboxylic acid (5). Both compounds 4 and 5 exhibited broad spectrum of high antibacterial activity against representatives of Gram-negative and Gram-positive bacteria classes, but were less potent than the reference ciprofloxacin.

Synthesis and Antibacterial Activity of Some Novel 4-Oxopyrido(2,3-a)phenothiazines

A series of substituted 4‐oxopyrido[2,3‐a]phenothiazine‐3‐carboxylic acids (6a–d) were prepared via cyclization of the corresponding ethyl 7‐(arylthioxy)‐8‐nitro(or azido)‐4‐oxoquinoline‐3‐carboxylates (3a–d/4a–d), followed by hydrolysis of the resultant esters (5a–d). Among these tetracyclics, compound 6a with unsubstituted terminal benzo‐ring D was the most active against representative Gram‐positive and Gram‐negative bacterial strains. These compounds were also active against methicillin‐resistant Staphylococcus aureus (MRSA), with very low toxicity to normal cells. Virtual screening using ligand–protein docking modeling predicted that the compounds 6a–d are potential inhibitors of the topoisomerase IV enzyme and that hydrophobic interactions and hydrogen bonds are the major molecular interactions between these compounds and the residues of the active site of topoisomerase IV.

Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway

Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent.

Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part XI: Synthesis and antibacterial activity of 4-fluoro-6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids

Abstract A series of 2-hetaryl-4-fluoro-9-cyclopropyl-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylic esters (3a–f) and their corresponding acids 4a–f have been prepared via microwave-assisted cyclocondensation reaction with some hetarene carboxaldehydes. The structures for these new esters and acids are based on spectral (IR, MS, and NMR) data. The in vitro antimicrobial assay of 4a–f hetaryl derivatives, their aryl analogues 1d–g, and the imidazo-unsubstituted acid 1a showed that all of these tricyclic heterocycles possess a good level of antibacterial activity. Among them, compound 1a exhibited the highest effect against both, Gram-positive (minimum inhibitory concentrations [MICs] 0.15–3.0 μg mL–1) and Gram-negative bacteria (MICs 0.7–3.0 μg mL–1). An excellent activity was recorded also for the halo-phenyl derivatives 1f,g and for the furan derivatives 4e,f, especially toward Gram-positive strains and Bacillus subtilis and Haemophilus influenzae, respectively.

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits.

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool ‘Emergent Self-Organizing Maps’ for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity.

Synthesis and Antitumor Activity of Some N2-(Thien-3-yl)amidrazones

6a A set of new N2-(thien-3-yl)amidrazones (-h) incorporating N-piperazines and related congeners has been synthesized by reacting the hydrazonoyl chloride 4(derived from 3-aminothiophene- 2-carboxylate) with the appropriate sec-cyclic amine. The antitumor activity of these compounds was evaluated on breast cancer (MCF-7) and leukemic (K562) cell lines by a cell viability assay utilizing the tetrazolium dye (MTT). The amidrazone 6d encompassing the N-piperazine moiety, was the most active against MCF-7 and K562 with IC50 of 7.28 and 9:91 μM, respectively. Graphical Abstract Synthesis and Antitumor Activity of Some N2-(Thien-3-yl)amidrazones

Design synthesis and antibacterial activity studies of new thiadiazoloquinolone compounds

Abstract New 9-(alkyl/aryl)-4-fluoro-6-oxo[1,2,5]thiadiazolo[3,4-h]quinoline-5-carboxylic acids and their esters were designed and synthesized. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported. All the newly synthesized compounds were fully characterized using all the physico-chemical means needed. All the intermediates and the final esters and acids were tested against bacterial and fungal strains. The acids 25a and 25c proved to be very active against Gram positive and Gram negative bacteria with MIC 0.15–3 µg/mL. The structure–activity relationship of antibacterial thiadiazoloquinolones shows that compounds 25a and 25c are twice less potent than the corresponding cyclopropyl derivative 16. Therefore, the cyclopropyl moiety on N-9 seems to be the most suitable substituent.

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid. Part XII: synthesis of 5-fluoro-7-oxodihydo[1,3,4]thiadiazino [5,6-h]quinoline-8-carboxylic acid and ester

Abstract Direct interaction of dithizone with 7-chloro-6- fluoro-8-nitro-4-oxoquinoline-3-carboxylic acid or with its ester delivered the corresponding novel 1,3,4-thiadiazino [5,6-h]quinoline 3-carboxylic acid, or its ester which was then hydrolyzed to the respective acid. Structures of the latter tricyclic hybrids were deduced from analytical and spectral data and confirmed by single crystal X-ray structure determination of the ester derivative. The free acid showed moderate activity against Staphylococcus aureus with a MIC value of 25 μg mL−1.

Heterocycles [c]-Fused onto Indoloquinoxaline. Synthesis of Novel Pyrano[2’,3’:4,5]indolo[2,3-b]quinoxalin-2-ones

A synthesis of 4-methylpyrano[2,3-e]indole-2,8,9-trione (5) is achieved from 7-amino-4- methylcoumarin by adopting the classical Sandmeyer methodology. The cyclocondensation reaction of pyrano-isatin 5 with the appropriately substituted o-phenylenediamines 6 in polyphosphoric acid proceeded regioselectively to furnish the respective pyrano[2’,3’:4,5]indolo[2,3-b]quinoxalines 7a - c. Structural assignments of the new compounds are based on microanalytical and spectral (IR, MS and NMR) data. Graphical Abstract Heterocycles [c]-Fused onto Indoloquinoxaline. Synthesis of Novel Pyrano[2’,3’:4,5]indolo[2,3-b]quinoxalin-2-ones