Soad A. M. El-Hawash

Synthesis of novel benzofuran and related benzimidazole derivatives for evaluation ofin vitro anti-HIV-1, anticancer and antimicrobial activities

Previously, we synthesized and evaluated several benzofuran derivatives containing heterocyclic ring substituents linked to the benzofuran nucleus at C-2 by a two- to four-atom spacer as potential anti-HIV-1, anticancer and antimicrobial agents. Among these derivatives,NSC 725612 andNSC 725716 exhibited interesting anti-HIV-1 activity. To further investigate the structure-activity relationship, we synthesized several new benzofuran derivatives derived from 2-acetylbenzofuran (2, 3a-c) and 2-bromoacetylbenzofuran (6; 7a,b; 8a,b). The compounds were designed to comprise the heterocyclic substituents directly linked to the benzofuran nucleus at C-2. Moreover, various related benzimidazoles derived from 2-acetylbenzimidazole and from 2-cyanomethylbenzimidazole (12a,b; 13a,b; 15; 16a,b) were also prepared as isosteres. The synthesized compounds were preliminarily evaluated for theirin vitro anti-HIV-1, anticancer and antimicrobial activity. Compounds2, 3a, 3b, and12b showed weak anti-HIV-1 activity. Compound6 exhibited mild activity againstS. aureus, while compound15 had mild activity towardsS. aureus andC. albicans. However, no significant anticancer activity was observed with any of the tested compounds. From these results, we conclude that the presence of the spacer between the heterocyclic substituent and the benzofuran nucleus may be essential for the biological activity.

Synthesis and in vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2)1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound5c was determined by X-ray crystallography. The compounds prepared were evaluated for theirin vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds5c and9a produced a significant reduction H 2 the viral cytopathic effect (93.19% and 59.55%) at concentrations >2.0×10−4 M and, 2.5×10−5 M respectively. Compound9a was confirmed to have moderate anti-HIV activity. Compounds2a, 2d, and5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.

Synthesis of thiazolo[4,5-d]pyrimidine derivatives as potential antimicrobial agents.

In this study, we report the synthesis and antimicrobial evaluation of several new thiazolo[4,5-d] pyrimidine derivatives, namely 7-substituted amino-5-methyl-3-phenylthiazolo[4,5-d]pyrimi-dine-2 (3H)-thiones4a- e,8,13,15, ethyl 2-cyano-2-(7-substituted-5-methyl-3-phenylthiazolo [4,5-d]-pyrimidin-2(3H)-ylidene)acetates5a- b, 2-(7-substituted-5-methyl-3-phenylthiazolo[4,5-d] pyrimidin-2(3H)-ylidene)malononitriles6a- b, 5-methyl-7-morpholino-3-phenylthiazolo[4,5-d] pyrimidine-2(3H)-one 7, and 7-[4-(1-substituted-5-phenyl-4,5-dihydro-1H-pyrazolin-3-yl)anilino]-5-methyl-3-phenylthiazolo[4,5-d]pyrimidine-2(3H)-thiones10- 12. Some of the tested compounds were more active againstC. albicans thanE. coli andP. aeruginosa, and all were inactive against S.aureus.

Synthesis and biological evaluation of novel series of thieno[2,3-d]pyrimidine derivatives as anticancer and antimicrobial agents

The present study is concerned with the synthesis, anticancer and antimicrobial screening of several new 3-substituted or 2,3-disubstituted-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide derivatives. Three compounds (4b, 8c, and 11b) were selected by the National Cancer Institute and were first evaluated at a single-dose primary anticancer assay against 60 human cancer cell lines for their in vitro anticancer activity. Compound 8c which passed the criteria for activity in this assay was evaluated against the full panel of 60 human cancer cell lines at five concentrations at tenfold dilutions where it showed non-selective broad-spectrum activity against all cancer cell lines. Furthermore, compounds 4b, 6, 8c, 8d, and 16 showed pronounced antibacterial activities comparable to ampicillin against P. aeruginosa. Therefore, it was concluded that compound 8c may serve as a useful lead compound in search for powerful dual anticancer-antimicrobial agents.

New hybrid molecules combining benzothiophene or benzofuran with rhodanine as dual COX-1/2 and 5-LOX inhibitors: Synthesis, biological evaluation and docking study

New molecular hybrids combining benzothiophene or its bioisostere benzofuran with rhodanine were synthesized as potential dual COX-2/5-LOX inhibitors. The benzothiophene or benzofuran scaffold was linked at position -2 with rhodanine which was further linked to various anti-inflammatory pharmacophores so as to investigate the effect of such molecular variation on the anti-inflammatory activity. The target compounds were evaluated for their in vitro COX/LOX inhibitory activity. The results revealed that, compound 5h exhibited significant COX-2 inhibition higher than celecoxib. Furthermore, compounds 5a, 5f and 5i showed COX-2 inhibitory activity comparable to celecoxib. Compound 5h showed selectivity index SI=5.1 which was near to that of celecoxib (SI=6.7). Compound 5h displayed LOX inhibitory activity twice than that of meclofenamate sodium. Moreover, compounds 5a, 5e and 5f showed significant LOX inhibitory activity higher than that of meclofenamate sodium. Compound 5h was screened for its in vivo anti-inflammatory activity using formalin-induced paw edema and gastric ulcerogenic activity tests. The results revealed that, it showed in vivo decrease in formalin-induced paw edema volume higher than celecoxib. It also displayed gastrointestinal safety profile as celecoxib. The biological results were also consistent with the docking studies at the active sites of the target enzymes COX-2 and 5-LOX. Also, compound 5h showed physicochemical, ADMET, and drug-like properties within those considered adequate for a drug candidate.

Design, synthesis and biological screening of some pyridinylpyrazole and pyridinylisoxazole derivatives as potential anti-inflammatory, analgesic, antipyretic and antimicrobial agents.

A series of substituted pyridinylpyrazole (or isoxazole) derivatives were synthesized and evaluated for their anti-inflammatory (AI) activity using formalin-induced paw edema bioassays. Their inhibitory activities of cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) were also determined. The analgesic activity of the same compounds was evaluated using rat-tail withdrawal technique. Their antipyretic activity was also evaluated. The results revealed that compounds 4a,b, 6a, 8a, 14c and 15a exhibited significant AI and analgesic activities. Compounds 5a, 6a and 8a displayed good antipyretic activity. Compounds 14c and 15a showed good COX-2 inhibitory activity and weak inhibition of COX-1. Additionally, the most active compounds were shown to have a large safety margin (ALD50 >300-400 mg / Kg) and minimal ulcerogenic potentialities when administered orally at a dose of 300 mg/Kg. Docking studies for 14c and 15a with COX-2 showed good binding profile. Antimicrobial evaluation proved that most of the compounds exhibited distinctive activity against the gram negative bacteria, P. aeruginosa and E coli.

Synthesis and Biological Evaluation of Some Novel Thieno[2,3-d] pyrimidine Derivatives as Potential Anti-inflammatory and Analgesic Agents

A novel series of thienopyrimidine derivatives bearing various substituents or linked to various heterocyclic moieties through atoms spacers were prepared starting from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6- carboxamide potassium salt 3. Twelve out of the prepared compounds were selected and evaluated for their antiinflammatory activity using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays using diclofenac sodium as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. In addition, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. The results revealed that compounds 5a, 13, 14b, 15a, 16a and 16b had high anti-inflammatory effect comparable to diclofenac sodium, whereas compounds 5a, 14a, 15a and 16a revealed pronounced analgesic activity that is equal or higher than that of the reference. All of the tested compounds revealed high GI safety profile and were well tolerated by the experimental animals with high safety margin (ALD50 > 3.0g/Kg).

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.

Design, synthesis, biological evaluation and docking studies of new 3-(4,5-dihydro-1 H -pyrazol/isoxazol-5-yl)-2-phenyl-1 H -indole derivatives as potent antioxidants and 15-lipoxygenase inhibitors

New candidates of 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives (4-7) were designed combining the pyrazoline/isoxazoline heterocycles and 2-phenylindole to explore its potential as 15-lipoxygenase (15-LOX) inhibitors. The design of the new derivatives was based on utilizing the antioxidant properties of pyrazoline, 2-phenylindole and the good 15-LOX inhibition properties of indolylpyrazoline. The derivatives were synthesized adopting simple and laboratory friendly reaction conditions to give the target compounds in quantitative yields. The resulting indolylpyrazolines/isoxazolines were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide dismutase (SOD); indolylpyrazoline (4b) was the most potent antioxidant against SOD assay (IC50 = 1.78 μM) to be superior to ascorbic by 2 folds. Consistently, (4b) was the most potent inhibitor when tested against Soybean 15-LOX (IC50 = 3.84 μM) excelling quercetin as standard inhibitor by 1.8 folds. Some of the new derivatives were docked into the active binding site of human 15-LOX (PDB entry 4NRE) emphasizing the most potent derivative (4b) and the least potent one (4c). Docking solutions of compounds (4b), (4c), (5b) and (6c) revealed that (4b) was the only compound that got stabilized into the catalytic pocket of enzyme by π-cation interaction with the catalytic Fe+ and formation of one hydrogen bond with Ile 676 amino acid. Other derivatives including the least potent one variably got stabilized into the active binding pocket by π-cation interaction with the catalytic Fe+ but failed to form hydrogen bond with Ile 676. For the future optimization of the generated inhibitors, (i) antioxidant activity against SOD, (ii) the inhibitor stabilization by π-cation interaction with the catalytic Fe+3 and (iii) formation of hydrogen bond with Ile 676 should be regarded.