Anisotropic Charge Distribution and Anisotropic van der Waals Radius Leading to Intriguing Anisotropic Noncovalent Interactions

Although group (IV-VII) nonmetallic elements do not favor interacting with anionic species, there are counterexamples including the halogen bond. Such binding is known to be related to the charge deficiency because of the adjacent atom's electron withdrawing effect, which creates s/p-holes at the bond-ends. However, a completely opposite behavior is exhibited by N-2 and O-2, which have electrostatically positive/negative character around cylindrical-bond-surface/bond-ends. Inspired by this, here we elucidate the unusual features and origin of the anisotropic noncovalent interactions in the ground and excited states of the 2nd and 3rd row elements belonging to groups IV-VII. The anisotropy in charge distributions and van der Waals radii of atoms in such molecular systems are scrutinized. This provides an understanding of their unusual molecular configuration, binding and recognition modes involved in new types of molecular assembling and engineering. This work would lead to the design of intriguing molecular systems exploiting anisotropic noncovalent interactions.open

Effects of Charge and Substituent on the S∙∙∙N Chalcogen Bond

Neutral complexes containing a S···N chalcogen bond are compared with similar systems in which a positive charge has been added to the S-containing electron acceptor, using high-level ab initio calculations. The effects on both XS···N and XS+···N bonds are evaluated for a range of different substituents X = CH3, CF3, NH2, NO2, OH, Cl, and F, using NH3 as the common electron donor. The binding energy of XMeS···NH3 varies between 2.3 and 4.3 kcal/mol, with the strongest interaction occurring for X = F. The binding is strengthened by a factor of 2–10 in charged XH2S+···NH3 complexes, reaching a maximum of 37 kcal/mol for X = F. The binding is weakened to some degree when the H atoms are replaced by methyl groups in XMe2S+···NH3. The source of the interaction in the charged systems, like their neutral counterparts, is derived from a charge transfer from the N lone pair into the σ*(SX) antibonding orbital, supplemented by a strong electrostatic and smaller dispersion component. The binding is also derived from small contributions from a CH···N H-bond involving the methyl groups, which is most notable in the weaker complexes

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity

Discovery of 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids as novel PPAR\u3b1 agonists with anti-hyperlipidemic and antioxidant activities: Design, synthesis and in vitro/in vivo biological evaluation

In the current work, a series of novel 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids (10a-o) and (11a-e) were synthesized and evaluated as new PPAR\u3b1 agonists in order to find new agents with higher activity and fewer side effects. The 2-propanoic acid derivative 10a and the 2-butanoic acid congener 10i showed the best overall PPAR\u3b1 agonistic activity showing Emax% values of 50.80 and 90.55%, respectively, and EC50 values of 8.9 and 25.0 \u3bcM, respectively, compared to fenofibric acid with Emax = 100% and EC50 = 23.22 \u3bcM, respectively. These two compounds also stimulated carnitine palmitoyltransferase 1A gene transcription in HepG2 cells and PPAR\u3b1 protein expression. Molecular docking simulations were performed for the newly synthesized compounds to study their predicted binding pattern and energies in PPAR\u3b1 active site to rationalize their promising activity. In vivo, compounds 10a and 10i elicited a significant hypolipidemic activity improving the lipid profile in triton WR-1339-induced hyperlipidemic rats, including serum triglycerides, total cholesterol, LDL, HDL and VLDL levels. Compound 10i possessed better anti-hyperlipidemic activity than 10a. At a dose of 200 mg/kg, it demonstrated significantly lower TC, TG, LDL and VLDL levels than that of fenofibrate at the same dose with similar HDL levels. Compounds 10i and 10a possessed atherogenic indices (CRR, AC, AI, CRI-II) like that of fenofibrate. Additionally, a promising antioxidant activity indicated by the increased tissue reduced glutathione and plasma total antioxidant capacity with decreased plasma malondialdehyde levels was demonstrated by compounds 10a and 10i. No histopathological alterations were recorded in the hepatic tissue of compound 10i (200 mg/kg)