Novel quinazolines bearing 1,3,4-thiadiazole-aryl urea derivative as anticancer agents: design, synthesis, molecular docking, DFT and bioactivity evaluations.

A novel series of 1-(5-((6-nitroquinazoline-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-phenylurea derivatives 8 were designed and synthesized to evaluate their cytotoxic potencies. The structures of these obtained compounds were thoroughly characterized by IR, 1H, and 13C NMR, MASS spectroscopy and elemental analysis methods. Additionally, their in vitro anticancer activities were investigated using the MTT assay against A549 (human lung cancer), MDA-MB231 (human triple-negative breast cancer), and MCF7 (human hormone-dependent breast cancer). Etoposide was used as a reference marketed drug for comparison. Among the compounds tested, compounds 8b and 8c demonstrated acceptable antiproliferative activity, particularly against MCF7 cells. Considering the potential VEGFR-2 inhibitor potency of these compounds, a molecular docking study was performed for the most potent compound, 8c, to determine its probable interactions. Furthermore, computational investigations, including molecular dynamics, frontier molecular orbital analysis, Fukui reactivity descriptor, electrostatic potential surface, and in silico ADME evaluation for all compounds were performed to illustrate the structure-activity relationship (SAR).

Synthesis and Antinociceptive Activity of Newly Modified Amine Analogs of Phencyclidine in Mice.

BACKGROUND: Phencyclidine (PCP, I) and its substituted analogs are significant and broadly abused psychotomimetic drugs that affect the central nervous system. They possess many pharmacological properties due to the presence of specific receptors in the brain. AIMS AND OBJECTIVE: Methyl group, despite strong electron-donating and characters of dipole moments, was placed on various positions of phenyl and amine moieties of phencyclidine along with the substitution of benzylamine, piperazine, and aniline derivatives in place of piperidine ring of phencyclidine to create novel compounds of the core with analgesic properties. MATERIALS AND METHODS: For evaluation of the analgesic activities of newly synthesized compounds, they were screened by tests of tail immersion (thermal) and formalin (chemical) pains. The obtained data with the control and PCP groups were also compared. RESULTS: The outcomes indicated that some new compounds have more antinociceptive effects than PCP in tail immersion and formalin tests. In the tail immersion test, the methyl piperazine analog (III) shows more efficacy than others. In the formalin test, none of the compounds are as effective as phencyclidine at the earliest time-point, but compounds IV and V show effectiveness during the second stage of formalin pain. CONCLUSION: It can be concluded that the methyl-piperazine analog of phencyclidine was the best candidate to decrease acute thermal pain, and benzylamine derivatives were suitable candidates to reduce chemical pains.

DFT (density functional theory) studies on cycloisomerization of 15-membered triazatriacetylenic macrocycle.

The mechanism as well the stereochemistry of cascade cycloisomerization of 15-membered triazatriacetylenic macrocycle was investigated theoretically by using M062X/6-31+G(d,p) and M062X/LANL2DZ calculations. The results showed that the mechanism and outcome of the reaction depended on the absence and presence of a transition metal catalyst. So that, in thermal-induced condition, the reaction had to experience several suprafacial concerted reactions including Ene-reaction (DG#=35.38 kcal/mol), Diels-Alder cycloaddition (DG# = 17.16 kcal/mol), and sigmatropic H-shift rearrangement (DG# = 56.21 kcal/mol) to produce diastereoselective fused cis-tetracyclic aromatic bearing a pyrrole moiety by following kinetic considerations. Also, the [2+2+2] cycloaddition mechanism was neglected in thermal-induced conditions because of high activation free Gibbs energy (DG# = 63.90 kcal/mol). In the presence of palladium catalyst, Pd(0) formed an adduct by coordinating to C = C bonds and decreased the DG# of the process to 29.58 kcal/mol, and consequently provided a facilitated media for the reaction to follow the [2+2+2] to produce more stable fused tetracyclic benzenoid aromatic by passing through the lower energy barrier.

New Amine and Aromatic Substituted Analogues of Phencyclidine: Synthesis and Determination of Acute and Chronic Pain Activities.

BACKGROUND: Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both. AIM AND OBJECTIVE: The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities. MATERIALS AND METHODS: Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups. RESULTS: The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site. CONCLUSION: It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.

Synthesis and in vitro cytotoxic activity of novel chalcone-like agents.

OBJECTIVE(S): Chalcones and their rigid analogues represent an important class of small molecules having anticancer activities. Therefore, in this study the synthesis and cytotoxic activity of new 3-benzylidenchroman-4-ones were described as rigid chalcone analogues. MATERIALS AND METHODS: The reaction of resorcinol with 3-chloropropionic acid in the presence of CF3SO3H was afforded corresponding propiophenone. It was cyclized using 2M NaOH to give 7-hydroxy-4-chromanone. O-Alkylation of 7-hydroxy-4-chromanone with alkyl iodide in the presence of K2CO3 gave 7-alkoxychroman-4-one. Finally, condensation of chroman-4-one derivatives with different aldehydes afforded target compounds in good yields. The newly synthesized compounds were tested in vitro against different human cancer cell lines including K562 (human erythroleukemia), MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cells. The cell viability was evaluated using MTT colorimetric assay. RESULTS: Most of the compounds showed good inhibitory activity against cancer cells. Among them, compound 4a containing 7-hydroxy group on chromanone ring and 3-bromo-4-hydroxy-5-methoxy substitution pattern on benzylidene moiety was the most potent compound with IC50 values ≤ 3.86 µg/ml. It was 6-17 times more potent than etoposide against tested cell lines. CONCLUSION: We described synthesis and cytotoxic activity of poly-functionalized 3-benzylidenechroman-4-ones as new chalcone-like agents. These compounds can be considered as conformationally constrained congeners of chalcones to tolerate the poly-functionalization on the core structures for further optimization.

Discovery of a novel nitroimidazolyl-oxazolidinone hybrid with potent anti Gram-positive activity: Synthesis and antibacterial evaluation.

A number of linezolid analogues containing a nitroaryl-1,3,4-thiadiazole moiety, were prepared and evaluated as antibacterial agents against a panel of Gram-positive and Gram-negative bacteria. Among synthesized compounds, nitrofuran analogue 1b exhibited more potent inhibitory activity, with respect to other synthesized compounds and reference drug linezolid. The target compounds were also assessed for their cytotoxic activity against normal mouse fibroblast (NIH/3T3) cells using MTT assay. The results indicated that compound 1c exhibit potent antibacterial activity against Gram-positive bacteria at non-cytotoxic concentrations.