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The current study reports the fabrication of co-combination gel using Pregabalin and Withania coagulans fruit extract to validate its effectiveness for neuropathic pain in chronic constriction injury (CCI) rat models. Three topical gels were prepared using Carbopol 934 through a pseudo-ternary phase diagram incorporating the Pregabalin (2.5%), Withania coagulans extract (2%), and co-combination of both Pregabalin (2.5%) and Withania coagulans extract (2%). Gels were characterized. FTIR showed a successful polymeric network of the gel without any interaction. The drug distribution at the molecular level was confirmed by XRD. The AFM images topographically indicated the rough surface of gels with a size range from 0.25 to 330 nm. DSC showed the disappearance of sharp peaks of the drug and extract, showing successful incorporation into the polymeric network of gels. The in vitro drug release of co-combination gel was 73% over 48 h. The mechanism of drug release by combination gel was Higuchi+ fickian with values of n (0.282) and R2 (0.947). An in vivo study for pain assessment via four methods: (i) heat hyperalgesia, (ii) cold allodynia, (iii) mechano-hyperalgesia, and (iv) dynamic mechano-allodynia, confirmed that topical treatment with co-combination gel reduced the pain significantly as indicated by the p value: R1 (p < 0.001), R2 (p < 0.001), R3 (p < 0.015), and R4 (p < 0.0344). The significance order was R2 (****) > R1 (***) > R3 (**) > R4 (*) > R5 (ns).

A novel series of amides based TMP moiety was designed, synthesized and evaluated for their antiproliferative as well as enzyme inhibition activity. Compounds 6a and 6b showed remarkable cytotoxic activity against HepG2 cells with IC50 values 0.65 and 0.92 μM, respectively compared with SAHA and CA-4 as reference compounds. In addition, compound 6a demonstrated good HDAC-tubulin dual inhibition activity as it showed better HDAC activity as well as anti-tubulin activity. Moreover, compound 6a exhibited G2/M phase arrest and pre-G1 apoptosis as demonstrated by cell cycle analysis and Annexin V assays. Further apoptosis studies demonstrated that compound 6a boosted the level of caspase 3/7. Caspase 3/7 activation and apoptosis induction were evidenced by decrease in mitochondrial permeability suggesting that activation of caspase 3/7 may occur via mitochondrial apoptotic pathway.

Dihydrouracil presents a crucial intermediate in the catabolism of uracil. The vital importance of uracil and its nucleoside, uridine, encourages scientists to synthesize novel dihydrouracils. In this paper, we present an innovative, fast, and effective method for the synthesis of dihydrouracils. Hence, under mild conditions, 3-chloroperbenzoic acid was used to cleave the carbon–sulfur bond of the Biginelli hybrids 5,6-dihydropyrimidin-4(3H)-ones. This approach led to thirteen novel dihydrouracils synthesized in moderate-to-high yields (32–99%).

New furan-based derivatives have been, designed, synthesized, and evaluated for their cytotoxic and tubulin polymerization inhibitory activities. DNA flow cytometric study of pyridine carbohydrazide 4 and N-phenyl triazinone 7 demonstrated G2/M phase cell cycle disruptions. Accumulation of cells in the pre-G1 phase and positive annexin V/PI staining, which may be caused by degeneration or fragmentation of the genetic components, suggested that cell death occurs via an apoptotic cascade. Furthermore, compounds 4 and 7 had a strong pro-apoptotic impact through inducing the intrinsic mitochondrial mechanism of apoptosis. This mechanistic route was verified by an ELISA experiment that indicated a considerable rise in the levels of p53 and Bax and a drop in the level of Bcl-2 when compared with the control.

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7–18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.