Controlling (E/Z)-Stereoselectivity of -NHC=O Chlorination: Mechanism Principles for Wide Scope Applications.

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation.

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198-0.096 µM, compared to IC50 value of 0.19420 µM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 µM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights.

Human health is experiencing several obstacles in the modern medical era, particularly cancer. As a result, the cancer therapeutic arsenal should be continually expanded with innovative small molecules that preferentially target tumour cells. In this study, we describe the development of two small molecule series (7a-d and 12a-e) based on the 1-benzyl-5-bromoindolin-2-one scaffold that connected through a hydrazone linker to a 4-arylthiazole (7a-d) or 4-methyl-5-(aryldiazenyl)thiazole (12a-e) moiety. The anticancer activity of all the reported indolin-2-one derivatives was assessed against breast (MCF-7) and lung (A-549) cancer cell lines. The 4-arylthiazole-bearing derivatives 7c and 7d revealed the best anticancer activity toward MCF-7 cells (IC50 = 7.17 ± 0.94 and 2.93 ± 0.47, respectively). Furthermore, the VEGFR-2 inhibitory activity for 7c and 7d was evaluated. Both molecules disclosed good inhibitory activity, and their IC50 values were equal to 0.728 µM and 0.503 µM, respectively. Additionally, the impacts of 7d on the cell cycle phases as well as on the levels of different apoptotic markers (caspase-3, caspase-9, Bax, and Bcl-2) were assessed. Molecular docking and dynamic simulations are carried out to explore the binding mode of 7d within the VEGFR-2 active site.

Thieno[2,3-c]isoquinolines: A novel chemotype of antiproliferative agents inducing cellular apoptosis while targeting the G2/M phase and Tubulin.

In the era of modern synthetic methodology and advanced bio-evaluation techniques and considering the notorious history of hepatocellular carcinoma (HCC), hopeful expectations regarding novel bioactive chemotypes have grown dramatically. Among the widely versatile motifs in drug discovery studies are isoquinoline and thieno[2,3-b]pyridine. Herein, the molecular merging of both motifs evoked thieno[2,3-c]isoquinoline as a novel antiproliferative chemotype being hardly studied against HCC. Accordingly, compound series 4, 5, 7 and 8 were synthesized and bioevaluated against the HepG2 cell line. The role of C7-Ac/C8-OH substituents, C8-C9 unsaturation, 1H-pyrrol-1-yl ring closure at C1-NH2 and C6-Ph p-halo-substitution were biologically studied and successfully furnished the lead 5b while showing safe profile against Vero cells. Further, flow cytometric and Annexin V-FITC/PI apoptotic bio-investigations of 5b unveiled remarkable cell cycle arrest at the G2/M phase besides a 60-fold increase in apoptosis. The use of a DFT conformational study followed by Molecular docking and molecular mechanics/generalized born surface area scoring evoked potential tubulin-targeting activity of 5b at colchicine-binding site, which was confirmed by experimental evidence (Tub Inhib IC50 = 71 µM vs. 14 µM for colchicine). Accordingly, preserving C7-acetyl and optimizing halogen position while preserving [6S,7R]-stereochemistry is crucial for optimum binding to colchicine binding site of tubulin.

Development of novel isatin thiazolyl-pyrazoline hybrids as promising antimicrobials in MDR pathogens.

Microbial Multidrug Resistance (MDR) is an emerging global crisis. Derivatization of natural or synthetic scaffolds is among the most reliable strategies to search for and obtain novel antimicrobial agents for the treatment of MDR infections. Here, we successfully manipulated the synthetically flexible isatin moieties to synthesize 22 thiazolyl-pyrazolines hybrids, and assessed their potential antimicrobial activities in vitro against various MDR pathogens, using the broth microdilution calorimetric XTT reduction method. We chose 5 strains to represent the major MDR microorganisms, viz: Methicillin-resistant S. aureus (MRSA), and Vancomycin-resistant E. faecalis (VRE) as Gram-positive bacteria; Carbapenem-resistant K. pneumonia (CRKP), and Extended-spectrum beta-lactamase E. coli (ESBL-E), as Gram-negative bacteria; and Fluconazole-resistant C. albicans (FRCA), as a yeast-like unicellular fungus. The cytotoxicity of compounds 9f and 10h towards mammalian lung fibroblast (MRC-5) cells demonstrated their potential satisfactory safety margin as represented by their relatively high IC50 values. The target compounds showed promising anti-MDR activities, suggesting they are potential leads for further development and in vivo studies.

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights.

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.

Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells.

As one of the most lethal malignancies, lung cancer is considered to account for approximately one-fifth of all malignant tumours-related deaths worldwide. This study reports the synthesis and in vitro biological assessment of two sets of 3-methylbenzofurans (4a-d, 6a-c, 8a-c and 11) and 3-(morpholinomethyl)benzofurans (15a-c, 16a-b, 17a-b and 18) as potential anticancer agents towards non-small cell lung carcinoma A549 and NCI-H23 cell lines, with VEGFR-2 inhibitory activity. The target benzofuran-based derivatives efficiently inhibited the growth of both A549 and NCI-H23 cell lines with IC50 spanning in ranges 1.48-47.02 and 0.49-68.9 µM, respectively. The three most active benzofurans (4b, 15a and 16a) were further investigated for their effects on the cell cycle progression and apoptosis in A549 (for 4b) and NCI-H23 (for 15a and 16a) cell lines. Furthermore, benzofurans 4b, 15a and 16a displayed good VEGFR-2 inhibitory activity with IC50 equal 77.97, 132.5 and 45.4 nM, respectively.

Tubulin inhibitors: Discovery of a new scaffold targeting extra-binding residues within the colchicine site through anchoring substituents properly adapted to their pocket by a semi-flexible linker.

Bis-hydrazides 13a-h were designed and synthesized as potential tubulin inhibitors selectively targeting the colchicine site between α- and ß-tubulin subunits. The newly designed ring-B substituents were assisted at their ends by 'anchor groups' which are expected to exert binding interaction(s) with new additional amino acid residues in the colchicine site (beyond those amino acids previously reported to interact with reference inhibitors as CA-4 and colchicine). Conformational flexibility of bis-hydrazide linker assisted these 'extra-binding' properties through reliving ligands' strains in the final ligand-receptor complexes. Compound 13f displayed the most promising computational and biological study results in the series: MM/GBSA binding energy of -62.362 kcal/mol (extra-binding to Arg α:221, Thr ß:353 & Lys ß:254); 34% NCI-H522 cells' death (at 10 µM), IC50 = 0.073 µM (MTT assay); significant cell cycle arrest at G2/M phase; 11.6% preG1 apoptosis induction and 83.1% in vitro tubulin inhibition (at concentration = IC50). Future researchers in bis-hydrazide tubulin inhibitors are advised to consider the 2-chloro-N-(4-substituted-phenyl)acetamide derivatives as compound 13f due to extra-binding properties of their ring B.

Synthesis, cytotoxicity, docking study, and tubulin polymerization inhibitory activity of novel 1-(3,4-dimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxanilides.

A series of novel 1-(3,4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives (4a-n) were synthesized and evaluated for their in vitro cytotoxic activity against the growth of four different human cell lines (hepatocarcinoma HepG2, breast adenocarcinoma MCF-7, colon carcinoma DLD-1, and leukemia HL-60). The anilides of m-anisidine 4e, o-anisidine 4f, and 3,5-difluoroaniline 4l demonstrated best results on MCF-7 cells and mean IC50 values of 7.79, 10.79, and 13.20 µM, respectively. The compounds produced a significant reduction in cellular microtubules at a concentration of 25 µg/mL, for microtubule loss. Molecular modeling studies involving compounds 4d, 4e, 4f, and 4l with the colchicine binding site of α,ß-tubulin revealed hydrogen bonding and hydrophobic interactions with several amino acids in the colchicine binding site of ß-tubulin.