Semicarbazides Carrying Indole Core: Synthesis, Cytotoxicity Evaluation against Human Breast Cancer Cell Lines, and Molecular Modeling Studies.

In this article, we report the synthesis and cytotoxicity evaluation of novel indole-carrying semicarbazide derivatives (IS1-IS15). The target molecules were obtained by the reaction of aryl/alkyl isocyanates with 1H-indole-2-carbohydrazide that was in-house synthesized from 1H-indole-2-carboxylic acid. Following structural characterization by 1 H-NMR, 13 C-NMR, and HR-MS, IS1-IS15 were investigated for their cytotoxic activity against human breast cancer cell lines, MCF-7 and MDA-MB-231. According to the data obtained from the MTT assay, phenyl ring with a lipophilic group at its para-position and alkyl moiety were preferential substituents on the indole-semicarbazide scaffold for antiproliferative activity. The effect of IS12 (N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(1H-indole-2-carbonyl)hydrazine-1-carboxamide), the compound that demonstrated remarkable antiproliferative activity on both cell lines, was also evaluated on the apoptotic pathway. Moreover, the calculation of critical descriptors constituting drug-likeness confirmed the position of the selected compounds in the anticancer drug development process. Finally, molecular docking studies suggested the inhibition of tubulin polymerization as the potential activity mechanism of this class of molecules.

Isolation, Characterization and in Silico Studies of Secondary Metabolites from Jurinea macrocephala DC. with Antiproliferative Activity.

In the present work, cytotoxic potential of Jurinea macrocephala DC. (Asteraceae) was evaluated on A549 lung cancer and MCF-7 breast cancer cell lines. Isolation studies were carried out using various and repetitive chromatographic methods in order to determine the phytochemical profile of the extracts. These studies led to the identification of twelve compounds; four triterpenes (1-4) and eight flavonoids (5-12). Spectroscopic examination (1D and 2D NMR, ESI-MS) and comparison with relevant literature data were used to deduce the structures of all isolated molecules. To rationalize the obtained cytotoxicity data against breast cancer cell lines, the isolated compounds were docked into the binding site of aromatase, an important target enzyme for the treatment of breast cancer. Molecular docking studies revealed that flavonoids without sugar moieties (5-8) showed the best binding affinities. Overall, these mentioned compounds turned out to be also the most appropriate oral drug candidates after the calculation of their Lipinski parameters.

Urea derivatives carrying a thiophenylthiazole moiety: Design, synthesis, and evaluation of antitubercular and InhA inhibitory activities.

The recent emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) has complicated and significantly slowed efforts to eradicate and/or reduce the worldwide incidence of life-threatening acute and chronic cases of tuberculosis. To overcome this setback, researchers have increased the intensity of their work to identify new small-molecule compounds that are expected to remain efficacious antimicrobials against Mtb. Here, we describe our effort to apply the principles of molecular hybridization to synthesize 16 compounds carrying thiophene and thiazole rings beside the core urea functionality (TTU1-TTU16). Following extensive structural characterization, the obtained compounds were initially evaluated for their antimycobacterial activity against Mtb H37Rv. Subsequently, three derivatives standing out with their anti-Mtb activity profiles and low cytotoxicity (TTU5, TTU6, and TTU12) were tested on isoniazid-resistant clinical isolates carrying katG and inhA mutations. Additionally, due to their pharmacophore similarities to the well-known InhA inhibitors, the molecules were screened for their enoyl acyl carrier protein reductase (InhA) inhibitory potentials. Molecular docking studies were performed to support the experimental enzyme inhibition data. Finally, drug-likeness of the selected compounds was established by theoretical calculations of physicochemical descriptors.

1,3-Disubstituted urea derivatives: Synthesis, antimicrobial activity evaluation and in silico studies.

The development of new antimicrobial compounds is in high demand to overcome the emerging drug resistance against infectious microbial pathogens. In the present study, we carried out the extensive antimicrobial screening of disubstituted urea derivatives. In addition to the classical synthesis of urea compounds by the reaction of amines and isocyanates, we also applied a new route including bromination, oxidation and azidination reactions, respectively, to convert 2-amino-3-methylpyridine to 1,3-disubstituted urea derivatives using various amines. The evaluation of antimicrobial activities against various bacterial strains, Candida albicans as well as Mycobacterium tuberculosis resulted in the discovery of new active molecules. Among them, two compounds, which have the lowest MIC values on Pseudomonas aeruginosa, were further evaluated for their inhibition capacities of biofilm formation. In order to evaluate their potential mechanism of biofilm inhibition, these two compounds were docked into the active site of LasR, which is the transcriptional regulator of bacterial signaling mechanism known as quorum sensing. Finally, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness properties.

Novel Quinoline-Based Thiosemicarbazide Derivatives: Synthesis, DFT Calculations, and Investigation of Antitubercular, Antibacterial, and Antifungal Activities.

The discovery of new antimicrobial agents as a means of treating drug-resistant microbial pathogens is of utmost significance to overcome their immense risk to human well-being. The current investigation involves the development, synthesis, and assessment of the antimicrobial efficacy of novel quinoline derivatives incorporating a thiosemicarbazide functionality. To design the target compounds (QST1-QST14), we applied the molecular hybridization approach to link various thiosemicarbazides to the quinoline core with a sulfonyl group. Upon the synthesis and completion of structural characterization via spectroscopic techniques (1H NMR, 13C NMR, 15N NMR, IR, and HRMS), the title molecules were extensively evaluated for their potential antitubercular, antibacterial, and antifungal activities. N-(3-Chlorophenyl)-2-(quinolin-8-ylsulfonyl)hydrazine-1-carbothioamide (QST4), the most effective compound against Mycobacterium tuberculosis H37Rv, was also tested on isoniazid-resistant clinical isolates with katG and inhA promoter mutations. Based on molecular docking studies, QST4 was also likely to demonstrate its antimycobacterial activity through inhibition of the InhA enzyme. Furthermore, three derivatives (QST3, QST4, and QST10) with preferable antimicrobial and drug-like profiles were also shown to be nontoxic against human embryonic kidney (HEK) cells. All compounds were optimized by the density functional theory method using B3LYP with the 6-31+G(d,p) basis set. Structural analysis, natural bond orbital calculations of donor-acceptor interactions, molecular electrostatic potential analysis, and frontier molecular orbital analysis were carried out. Quantum chemical descriptors and charges on the atoms were determined to compare the strengths of the intramolecular hydrogen bonds formed and their stabilities. We determined that the sulfur atom forms a stronger intramolecular hydrogen bond than the nitrogen, oxygen, and fluorine atoms in these sulfonyl thiosemicarbazide derivatives.

Two new eudesmane-type sesquiterpene derivatives from Lecokia cretica (Lam.) DC.

Two new sesquiterpene glucosides, 1α,6ß,9ß-trihydroxy-eudesm-4(15)-en-1,6-O-ß-diglucopyranoside (1) and 1α,6ß,9ß-trihydroxy-eudesm-3-en-1,6-O-ß-diglucopyranoside (2) were obtained along with the 1α,6ß,9ß-trihydroxy-5,10-bis-epi-eudesm-3-en-6-O-ß-D-glucopyranoside (3), chlorogenic acid (4), luteolin 7-O-rutinoside (5) and luteolin 7-O- glucoside (6) from the whole plant parts of Lecokia cretica. Their structures were determined on the basis of 1 D, 2 D NMR and HRMS analyses. The in vitro cytotoxic activity of compounds 1-3 against human lung cancer cells (A549) and normal human lung cells (BEAS-2B) was determined using the MTT colorimetric assay. All the tested eudesmane derivatives were found to be inactive.

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity.

Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1-SIH13). Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1-SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1-SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1-SIH13 adhered to Lipinski's rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb.

Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.

Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code: 5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using 1H NMR, 13C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 µg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.

Discovery of hydrazone containing thiadiazoles as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.

Tuberculosis, caused by Mycobacterium tuberculosis, is a serious infectious disease and remains a global health problem. There is an increasing need for the discovery of novel therapeutic agents for its treatment due to the emerging multi-drug resistance. Herein, we present the rational design and the synthesis of eighteen new thiadiazolylhidrazones (TDHs) which were synthesized by intramolecular oxidative N-S bond formation reaction of 2-benzylidene-N-(phenylcarbamothioyl)hydrazine-1-carboximidamide derivatives by phenyliodine(III) bis(trifluoroacetate) (PIFA) under mild conditions. The compounds were characterized by various spectral techniques including FTIR, 1H NMR, 13C NMR and HRMS. Furthermore, the proposed structure of TDH12 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Among them, some compounds exhibited remarkable antimycobacterial activity, MIC = 0.78-6.25 µg/mL, with low cytotoxicity. Additionally, the most active compounds were screened for their biological activities against M. tuberculosis in the nutrient starvation model. Enzyme inhibition assays and molecular docking studies revealed enoyl acyl carrier protein reductase (InhA) as the possible target enzyme of the compounds to show their antitubercular activities.