Novel phenylthiazoles with a tert-butyl moiety: promising antimicrobial activity against multidrug-resistant pathogens with enhanced ADME properties.

The structure-activity relationship of a new tert-butylphenylthiazole series, with a pyrimidine linker, was investigated. We wished to expand knowledge of this novel class of antibiotics by generating 21 new derivatives bearing ≥2 heteroatoms in their side chains. Their activity was examined against isolates of methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, Escherichia coli, Neisseria gonorrhoeae, and Candida albicans. Two compounds with 1,2-diaminocyclohexane as a nitrogenous side chain showed promising activity against the highly infectious MRSA USA300 strain, with a minimum inhibitory concentration (MIC) of 4 µg mL-1. One of these two compounds demonstrated potent activity against C. difficile, with a MIC of 4 µg mL-1. Moderate activities against a C. difficile strain with a MIC of 8 µg mL-1 were noted. Some new compounds possessed antifungal activity against a wild fluconazole-resistant C. albicans strain, with MIC values of 4-16 µg mL-1. ADME and metabolism-simulation studies were performed for the most promising compound and compared with lead compounds. Our results revealed that one compound possessed greater penetration of bacterial membranes and metabolic resistance, which aided a longer duration of action against MRSA.

New thiazolidine-2,4-diones as effective anti-proliferative and anti-VEGFR-2 agents: Design, synthesis, in vitro, docking, MD simulations, DFT, ADMET, and toxicity studies.

Novel thiazolidine-2,4-dione derivatives, 11a-g, were designed, and synthesized targeting the VEGFR-2 protein. The in vitro studies indicated the abilities of the synthesized derivatives to inhibit VEGFR-2 and prevent the growth of two different cancer cell types, HepG2 and MCF-7. Compound 11 f exhibited the strongest anti-VEGFR-2 activity (IC50 = 0.053 µM). As well, compound 11 f showed impressive anti-proliferative activity against the mentioned cancer cell lines with IC50 values of 0.64 ± 0.01 and 0.53 ± 0.04 µM, respectively. Additionally, compound 11 f arrested the MCF-7 cell cycle at the S phase and increased the overall apoptosis percentage. Furthermore, cell migration assay revealed that compound 11 f has a significant ability to prevent migration and healing potentialities of MCF-7. Moreover, computational studies were used to conduct the molecular investigation of the VEGFR-2-11 f complex. The kinetic and structural features of the complex were examined using molecular dynamics simulations and molecular docking. Besides, Principal component analysis (PCA) was used to explain the dynamics of the VEGFR-2-11 f complex at various spatial scales. The DFT calculations also provided further clarity regarding compound 11 f's structural and electronic features. To evaluate how closely the developed compounds might look like drugs, ADMET and toxicity experiments were computed. To conclude, the presented study demonstrates the potential of compound 11 f as a viable anti-cancer drug, which can serve as a prototype for future structural modifications and further biological investigations.

In vitro and in silico evaluation of new thieno[2,3-d]pyrimidines as anti-cancer agents and apoptosis inducers targeting VEGFR-2.

In this study, new thieno[2,3-d]pyrimidine derivatives that could have potential anticancer activity by inhibiting the VEGFR-2 receptor have been designed, synthesized, and investigated. The thieno[2,3-d]pyrimidine derivatives showed strong in vitro abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two different types of cancer cells, MCF-7 and HepG2. Particularly, compound 22 showed the most potent anti-VEGFR-2 activity with an IC50 value of 0.58 µM. Additionally, compound 22 exhibited good anti-proliferative activity against both MCF-7 and HepG2 cancer cell lines, with IC50 values of 11.32 ± 0.32 and 16.66 ± 1.22 µM, respectively. Further investigations revealed that compound 22 induced cell cycle arrest at the G2/M phase and promoted both early and late apoptosis in the MCF-7 cancer cells. Compound 22 also increased the level of BAX (2.8-fold), and reduced the level of Bcl-2 (2.2-fold), hence increasing the rate of apoptosis. Compound 22 also revealed 2.9-fold and 2.8-fold higher levels of caspase-8 and caspase-9, respectively, in the treated MCF-7 cancer cells compared to the control cell lines. The MD simulations showed that the VEGFR-2-22 complex was structurally and energytically stable over 100 ns, while the MM-GBSA study indicated its stable thermodynamic behavior. The bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-22 complex, while the DFT studies provided optimized geometry, charge distribution, FMO, ESP, the total density of state, and QTAIM maps of compound 22. Finally, computational ADMET studies were performed to assess the drug development potential of the thieno[2,3-d]pyrimidine derivatives. Overall, this study suggests that compound 22 has the potential as an anticancer lead compound by inhibiting VEGFR-2, which may be a guide for future drug design and development.

Exploring the structure-activity relationships of diphenylurea as an antibacterial scaffold active against methicillin- and vancomycin-resistant Staphylococcus aureus.

A set of structurally related diphenylurea derivatives bearing aminoguanidine moiety were synthesized, and their antibacterial activity was assessed against a panel of multi-drug resistant Gram-positive clinical isolates. Two compounds 6 and 24 were identified with better bacteriological profile than the lead compound I. The multi-step resistance development studies indicated that MRSA are less likely to develop resistance toward diphenylurea compounds. Moreover, these compounds demonstrated a prolonged post-antibiotic effect than that of vancomycin. Furthermore, compounds 6 and 24 were able to re-sensitize VRSA to vancomycin, resulting in 8- to more than 32-fold improvement in vancomycin MIC values against clinical VRSA isolates. Finally, when assessed in an in vivo skin infection mouse model, the efficacy of compound 24 was very comparable to that of the commercially available fusidic acid ointment. Additionally, the diphenylurea 24 did not have a pronounced effect on the animal weights along the experiment indicating its safety and tolerability to mice. Taken together, these results indicate that the diphenylurea scaffold merits further investigation as a promising anti-staphylococcal treatment option.

1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.

In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.