Synthesis of pyrazolo-1,2,4-triazolo[4,3-a]quinoxalines as antimicrobial agents with potential inhibition of DHPS enzyme.

AIM: The development of a new class of antimicrobial agents is the optimal lifeline to scrap the escalating jeopardy of drug resistance. EXPERIMENTAL: This study aims to design and synthesize a series of pyrazolo-1,2,4-triazolo[4,3-a]quinoxalines, to develop agents having antimicrobial activity through potential inhibition of dihyropteroate synthase enzyme. The target compounds have been evaluated for their in-vitro antimicrobial activity. RESULTS & DISCUSSION: Compounds 5b, 5c were equipotent (minimal inhibitory concentration = 12.5 µg/ml) to ampicillin. The docking patterns of 5b and 5c demonstrated that both fit into Bacillus Anthracis dihydropteroate synthase pterin and p-amino benzoic acid-binding pockets. Moreover, their physicochemical properties and pharmacokinetic profiles recommend that they can be considered drug-like candidates. The results highlight some significant information for the future design of lead compounds as antimicrobial agents.

Design, synthesis, antibacterial evaluation and molecular docking studies of some new quinoxaline derivatives targeting dihyropteroate synthase enzyme.

Development of new antimicrobial agents is a good solution to overcome drug-resistance problems. From this perspective, new quinoxaline derivatives bearing various bioactive heterocyclic moieties (thiadiazoles, oxadiazoles, pyrazoles and thiazoles) were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro antibacterial activity against nine bacterial human pathogenic strains using the disc diffusion assay. In general, most of the synthesized compounds exhibited good antibacterial activities. The thiazolyl 11c displayed significant antibacterial activities against P. aeruginosa (MIC, 12.5 µg/mL vs levofloxacin 12.5 µg/mL). Molecular docking studies indicated that the synthesized compounds could occupy both p-amino benzoic acid (PABA) and pterin binding pockets of the dihydropteroate synthase (DHPS), suggesting that the target compounds could act by the inhibition of bacterial DHPS enzyme. The results provide important information for the future design of more potent antibacterial agents.

Novel quinuclidinone derivatives induced apoptosis in human breast cancer via targeting p53.

Small molecules that can target human cancers have been highly sought to increase the anticancer efficacy, the present work describes the design and synthesis of novel series of five quinuclidinone derivatives (2a-2e). Their anticancer activities were investigated against breast cancer cells MCF-7, MDA-MB-231 breast cancer cells harboring mutant p53 and normal breast counterpart MCF-12a. Derivative 2e reduced proliferation of MCF-7 and MCF-12a while it has no effect on MDA-MB-231. Derivative 2e induced apoptosis in MCF-7 cells which is further confirmed by TUNEL assay and it reduced the percentage of cell in G2/M phase as confirmed by increased expression of cyclin B and reduced expression of cyclin D1. Derivative 2e reduced expression levels of Mdm2, Akt and ERK1/2 by and increased expression level of p53. Moreover, the apoptosis induction by 2e was also inhibited by PFT-α as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both derivative 2e and PFT-α. In addition, docking study reveals that derivative 2e has a binding pattern close to the pattern observed in the structure of the lead fragment 5,6-dimethoxy-2-methylbenzothiazole bound to T-p53C-Y220C. The above findings demonstrate that derivative 2e induces apoptosis in MCF-7 cells via targeting p53 which merits further development.

Synthesis of some new amide-linked bipyrazoles and their evaluation as anti-inflammatory and analgesic agents.

Four series of new bipyrazoles comprising the N-phenylpyrazole scaffold linked to polysubstituted pyrazoles or to antipyrine moiety through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory and analgesic activities. In vitro COX-1/COX-2 inhibition study revealed that compound 16b possessed the lowest IC50 value against both COX-1 and COX-2. Moreover, the effect of the most promising compounds on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) protein expression in lipopolysaccharide (LPS)-activated rat monocytes was also investigated. The results revealed that some of the synthesized compounds showed anti-inflammatory and/or analgesic activity with less ulcerogenic potential than the reference drug diclofenac sodium and are well tolerated by experimental animals. Moreover, they significantly inhibited iNOS and COX-2 protein expression induced by LPS stimulation. Compounds 16b and 18 were proved to display anti-inflammatory activity superior to diclofenac sodium and analgesic activity equivalent to it with minimal ulcerogenic potential.

Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells.

Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds 7a and 7b comprising aminoguanidino or guanidino moiety at position 6 inhibited proliferation of RKO colon cancer cells with IC50 of 8 and 4 µM, respectively. Compounds 7a and 7b induced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds 7a and 7b arrested RKO cells in the G1 phase and the most active compound 7b increased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound 7b also activates release of cytochrome c, which is consistent with activation of caspase-9. Additionally, compound 7b increased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents.

Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling.

In this study, novel thiosemicarbazides and 1,3,4-oxadiazoles were synthesized and evaluated for their anticancer effects on human MCF-7 breast cancer cell lines. Among the synthesized derivatives studied, compound 2-(3-(4-chlorophenyl)-3-hydroxybutanoyl)-N-phenylhydrazinecarbothioamide 4c showed the highest cytotoxicity against MCF-7 breast cancer cells as it reduced cell viability to approximately 15% compared to approximately 25% in normal breast epithelial cells. Therefore, we focused on 4c for further investigations. Our data showed that 4c induced apoptosis in MCF-7 cells which was further confirmed by TUNEL assay. Western blotting analysis showed that compound 4c up-regulated the pro-survival proteins Bax, Bad and ERK1/2, while it down-regulated anti-apoptotic proteins Bcl-2, Akt and STAT-3. Additionally, 4c induced phosphorylation of SAPK/JNK in MCF-7 cells. Pretreatment of MCF-7 cells with 10 µM of JNK inhibitor significantly reduced 4c-induced apoptosis. Molecular docking results suggested that compound 4c showed a binding pattern close to the pattern observed in the structure of the lead fragment bound to JNK1. Collectively, the data of current study suggested that the thiosemicarbazide 4c might trigger apoptosis in human MCF-7 cells by targeting JNK signaling.

Computer-aided design, synthesis, and biological evaluation of 5- substituted aminomethylenepyrimidine-2,4,6-triones as H1 antihistaminic agents (Part2).

As a part of a research project pertaining to the synthesis of novel candidates as nonsedating, nonclassic H1 histaminergic (H1) blockers with low toxicity profiles, some new 5-substituted aminomethylenepyrimidine-2,4,6-triones were designed based on the H1 histaminic receptor pharmacophore model. The interactions between the designed compounds and the H1 receptor were studied using molecular docking on the homology model of H1 receptor. The designed compounds were synthesized and biologically evaluated for H1-blocking activity; using isolated segments of guinea pig ileum. Compounds 15,18,19 and 21 exhibited comparable activities to acrivastine (22) as reference nonsedating drug. The C log P of designed compounds revealed lower values in reference to acrivastine (22) which might indicate decreased tendency for crossing the blood brain barrier.

Design, synthesis and molecular docking study of some substituted 4,5- dihydro-2H-indazole derivatives as potential anti-inflammatory agents.

A new series of 4,5-dihydro-2H-indazoles was synthesized and evaluated for anti-inflammatory activity using formalin-induced paw edema and turpentine oil-induced granuloma pouch bioassays. In addition, the inhibitory activity of cyclooxygenase, ulcerogenic effect, and acute toxicity (ALD50) values were also determined. Compounds 10, 13, 15, 16, 18 and 22 were proved to display distinctive anti-inflammatory profiles with a fast onset of action. They revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD50 >300 mg/Kg). The same active compounds exhibited moderate to powerful selectivity profile towards the inhibition of COX-2 enzyme. Docking poses for the most active compounds separately in the active site of human COX-2 enzyme were also obtained.

Synthesis and anticancer activity of novel benzimidazole and benzothiazole derivatives against HepG2 liver cancer cells.

Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.