Mona H. Badr

Design and synthesis of some thiazolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory, analgesic and antimicrobial agents ☆

The synthesis of two groups of structure hybrids comprising basically the antipyrine moiety attached to either polysubstituted thiazole or 2,5-disubstituted-1,3,4-thiadiazole counterparts through various linkages is described. Twelve out of the newly synthesized compounds were evaluated for their anti-inflammatory activity using two different screening protocols; namely, the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays, using diclofenac Na as a reference standard. The ulcerogenic effects and acute toxicity (ALD(50)) values of these compounds were also determined. Meanwhile, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. Additionally, the synthesized compounds were evaluated for their in vitro antimicrobial activity. In general, compounds belonging to the thiazolylantipyrine series exhibited better biological activities than their thiadiazolyl structure variants. Collectively, compounds 6, 10, 26, and 27 proved to display distinctive anti-inflammatory and analgesic profiles with a fast onset of action. All of the tested compounds revealed super GI safety profile and are well tolerated by the experimental animals with high safety margin (ALD(50)>3.0 g/kg). Meanwhile, compounds 7, 10, 11, and 23 are considered to be the most active broad spectrum antimicrobial members in this study. Compound 10 could be identified as the most biologically active member within this study with an interesting dual anti-inflammatory analgesic and antibacterial profile.

Synthesis of Some Pyrazolines and Pyrimidines Derived from Polymethoxy Chalcones as Anticancer and Antimicrobial Agents

The synthesis of a series of certain polymethoxy chalcones and some derived pyrazole, pyrimidine, and thiazolopyrimidine ring structures is reported. Eleven compounds 4, 6, 9, 11, 14–17, 22, 24, and 25 were selected by the National Cancer Institute (NCI) to be screened for their in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compounds 4, 6, and 11 were found to possess a significant broad spectrum antitumor potential against most of the tested subpanel tumor cell lines. The pyrazolines 4 and 6 displayed remarkable growth inhibitory activities (GI50 MG‐MID values of 2.10 and 1.38 µM, respectively), together with moderate cytostatic effects (TGI MG‐MID values of 47.9 and 42.7 µM, respectively). Meanwhile, the pyrimidin‐2‐one 11 showed a noticeable overall tumor growth inhibitory activity, together with high cytostatic and cytotoxic efficacies (GI50, TGI and LC50 MG‐MID values of 3.39, 17.4, and 61.7 µM, respectively). On the other hand, compounds 3, 4, 13, 15, 19, 20, and 23 were found to be the most active antimicrobial members in this investigation with a broad spectrum of activity. Compound 23 was four times superior to ampicillin against Pseudomonas aeruginosa. The best antifungal activity was demonstrated by compounds 4, 5, and 11 which possessed almost half the activity of clotrimazole against Candida albicans. Collectively, the obtained biological results suggest that compound 4 could be considered as a possible dual antimicrobial‐anticancer agent.

Bifunctional ethyl 2-amino-4-methylthiazole-5-carboxylate derivatives: Synthesis and in vitro biological evaluation as antimicrobial and anticancer agents

Thirty thiazole compounds bearing chemotherapeutically-active pharmacophores were synthesized and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Nineteen compounds displayed obvious antibacterial potential, with special bactericidal activity against Gram positive bacteria, whereas, nine analogs showed moderate to weak antifungal activity against Candida albicans. The analog 12f proved to be the most active antimicrobial member identified in this study being comparable to ampicillin and gentamicin sulfate against Staphylococcus aureus and Bacillus subtilis, together with a moderate antifungal activity. Additionally, nine derivatives were tested for their preliminary in vitro anticancer activity according to the current one-dose protocol of the NCI. Compound 9b revealed a broad spectrum of anticancer activity against 29 out of the tested 60 subpanel tumor cell lines. Collectively, compounds 4, 9b, 10b and 12f could be considered as promising dual anticancer antibiotics.

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.

Benzodioxole–Pyrazole Hybrids as Anti-Inflammatory and Analgesic Agents with COX-1,2/5-LOX Inhibition and Antioxidant Potential

Two series of benzodioxole–pyrazole hybrids were synthesized and the IC50 values for in vitro inhibition of the enzymes cyclooxygenase 1/2 (COX‐1, COX‐2) and 5‐lipoxygenase (5‐LOX) were investigated. All compounds were tested for their in vivo anti‐inflammatory and analgesic potentials using diclofenac sodium as a reference standard. Compounds 4, 11, 17, 20, 21, 26, and 27, which showed good analgesic and/or anti‐inflammatory activities, were also evaluated for their ability to inhibit tumor necrosis factor (TNF)‐α production, myeloperoxidase and proteinase, beside their antioxidant activity. Collectively, compounds 11, 17, and 26 displayed significant anti‐inflammatory, analgesic, and antioxidant activities, beside dual COX‐2 and 5‐LOX inhibition. Among these, compound 26 showed high selectivity for in vitro COX‐1/COX‐2 inhibition, whereas the analogs 11 and 17 noticeably ameliorated the TNF‐α level by 85.19 and 97.71%, respectively. A molecular docking study was performed to investigate the possible binding mode of compounds 11, 17, and 26 with the active sites of the COX‐2 and 5‐LOX enzymes, where they showed nearly the same binding pattern as that of celecoxib and meclofenamic acid, respectively.

Synthesis of Some 1,4,6-Trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles and Their Biological Evaluation as Cytotoxic and Antimicrobial Agents.

A series of novel 1,4,6‐trisubstituted‐2‐oxo‐1,2‐dihydropyridine‐3‐carbonitriles supported with some functionalities reported to contribute to significant chemotherapeutic potential were synthesized and evaluated for their antimicrobial and/or cytotoxic activities. Thirteen compounds exhibited cytotoxic potential against a panel of three human tumor cell lines. Compounds 15, 23, and 24 proved to be the most active agents with a broad spectrum of cytotoxic activity. Analog 24 was considered as the most active cytotoxic agent, being 2.5 times more active than doxorubicin against the colon HT29 carcinoma cell line. Seventeen compounds were able to exert a variable antimicrobial profile, among which analogs 15, 20, 21, 23, and 24 were prominently active. The highest antimicrobial potential was displayed by analog 24, being equipotent to ampicillin against Staphylococcus aureus and Escherichia coli, together with a considerable antifungal activity comparable with clotrimazole. Collectively, compounds 15, 23, and 24 could be considered as possible dual antimicrobial‐anticancer candidates.

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.

1,4-Disubstituted-5-hydroxy-3-methylpyrazoles and some derived ring systems as cytotoxic and DNA binding agents. Synthesis, in vitro biological evaluation and in silico ADME study

Some novel polysubstituted pyrazoles, bipyrazoles and pyranopyrazoles, supported with various chemotherapeutically-active pharmacophores, were synthesized and biologically evaluated for their cytotoxic potential. Fifteen compounds (7–9, 12, 16, 17, 19, 21, 22, 26, 28, 30, 32, 33, and 34) exhibited variable degrees of cytotoxic activity against a panel of three cancer cell lines, among which the analogs 16, 17, 21, 26, and 34 showed a considerable broad spectrum cytotoxic potential, with special effectiveness against the colon HT29 and breast MCF7 cancer cell lines. In particular, compounds 16, 17, and 26 displayed double the activity of doxorubicin against colon carcinoma HT29 cell line, while the pyranopyrazole analog 34 was nearly equiactive with the reference cytotoxic agent. Meanwhile, the analogs 16 and 17 were nearly equipotent to doxorubicin against breast MCF7 cell line. DNA-binding activities of the most active compounds were in agreement with the obtained anticancer activity, where compounds 16, 17, 26, and 34 displayed the highest affinity. In silico calculations of molecular properties revealed that most of the active compounds comply with Lipinski’s RO5 and Veber’s criteria for good bioavailability suggesting good drug-likeness properties upon oral administration.Some novel polysubstituted pyrazoles, bipyrazoles and pyranopyrazoles, supported with various chemotherapeutically-active pharmacophores, were synthesized and biologically evaluated for their cytotoxic potential. Fifteen compounds (7–9, 12, 16, 17, 19, 21, 22, 26, 28, 30, 32, 33, and 34) exhibited variable degrees of cytotoxic activity against a panel of three cancer cell lines, among which the analogs 16, 17, 21, 26, and 34 showed a considerable broad spectrum cytotoxic potential, with special effectiveness against the colon HT29 and breast MCF7 cancer cell lines. In particular, compounds 16, 17, and 26 displayed double the activity of doxorubicin against colon carcinoma HT29 cell line, while the pyranopyrazole analog 34 was nearly equiactive with the reference cytotoxic agent. Meanwhile, the analogs 16 and 17 were nearly equipotent to doxorubicin against breast MCF7 cell line. DNA-binding activities of the most active compounds were in agreement with the obtained anticancer activity, where compounds 16, 17, 26, and 34 displayed the highest affinity. In silico calculations of molecular properties revealed that most of the active compounds comply with Lipinski’s RO5 and Veber’s criteria for good bioavailability suggesting good drug-likeness properties upon oral administration.

Dual inhibitors of hepatitis C virus and hepatocellular carcinoma: design, synthesis and docking studies

Aim: Simultaneous inhibition of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may enhance anti-HCV effects and reduce resistance and side effects. Results/methodology: Novel hybrid derivatives were designed and synthesized to exhibit dual activity against HCV and its associated major complication, HCC. The synthesized compounds were screened for their potential activity against HCV and HCC. Compounds 5f, 5j, 5l, 5p, 5q, 5r, 6c and 6d exhibited potential in vitro anticancer activity against HCC cell line HepG2, while compounds 5a, 5l, 5p and 5v showed in vitro anti-HCV activity. Docking studies suggested that the newly synthesized compounds could suppress HCC through VEGFR2 tyrosine kinase inhibition. Conclusion: Compounds 5l and 5p exhibited dual activity against HCV and HCC in vitro.

Novel Polyfunctional Pyridines as Anticancer and Antioxidant Agents. Synthesis, Biological Evaluation and in Silico ADME-T Study

Two series of novel alkoxylated 2-oxo(imino)-3-pyridinecarbonitriles (structurally-relevant to some reported anticancer pyridines with phosphodiesterase 3A (PDE3A) inhibitory activity) were synthesized and evaluated for their in vitro differential tumor cell growth inhibitory potential against the breast MCF7, hepatocellular Hep-G2, colon CACO-2 cell lines, and a normal human foreskin fibroblast Hs27 cell line. Compounds 8, 16 and 19 displayed recognizable growth inhibitory ability and selectivity towards the breast MCF7 (LC50 19.15, 17.34 and 14.70 µM, respectively) as compared with doxorubicin (LC50 3.94 µM). Meanwhile, compounds 8, 15, 16, and 19 revealed a marginal inhibitory effect on the growth of the normal human foreskin fibroblast Hs27 cell line, beside a distinctive antioxidant potential in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. These four compounds were further assessed for their in vitro inhibition of PDE3A (a current antitumor therapeutic target), where 16 and 19 showed moderate to weak PDE3A inhibitory as compared with milrinone, the positive control. No clear straightforward liaison between the anticancer potential and PDE3A inhibitory activity could be deduced. Computations of the predicted pharmacokinetic properties, toxicity effects (ADME-T), drug-likeness and drug scores for the newly developed compounds showed non-violations of Lipinskis RO5 and Vebers criteria for good bioavailability, with a predicted high safety profile.