Kamilia M. Amin

Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents.

Two groups of coumarin-pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC(50) ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α).

Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines.

Novel series of bicyclic pyrrolo[1,2-c]pyrimidines 3a-g, 5, 6a, b, and 7a, b, tricyclic pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines 8a-c, 9a-g, 13a-c, 17, 18a, b, 19, 20a,b and 21 and tetracyclic condensed pyrimidines 14, 22 and 23 were synthesized through different chemical reactions. Structures of all synthesized pyrimidine derivatives were supported by spectral and elemental analyses. Analgesic activity evaluation was carried out using acetic acid-induced writhing assay, and all compounds exerted comparable activity to indomethacin. The anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema in rats, the potency of the bicyclic derivatives 3a-f and 7b revealed comparable activity to indomethacin without gastric ulceration. The tricyclic derivatives 13a and 20a exerted good activity, however, they induced gastric ulcers while 13b and 13c showed moderate activity without ulceration. In case of tetracyclic derivatives, compound 14 exhibited the highest potency and safety profile.

Design, synthesis and vasorelaxant evaluation of novel coumarin-pyrimidine hybrids.

The main objective of the present work depends on the hybridization of coumarin moiety as a vasorelaxant scaffold and pyrimidine ring with known potential cardiovascular activity in order to prepare some new potent antihypertensive candidates. Hence, two groups of pyrimidinyl coumarin derivatives were synthesized and evaluated for their vasorelaxing activity. These compounds were prepared via two routes; either preparation of the guanidinocoumarin 4 followed by a cocktail of cyclization reactions to yield a different array of 6-(substituted pyrimidin-2-yl)aminocoumarins 5-17, or through cyclization of the precursor chalcones 22a-g with guanidine hydrochloride to generate the corresponding final compounds, 8-(6-aryl-2-aminopyrimidin-4-yl)-7-methoxycoumarins 23a-g. The effect of these compounds and the coumarin intermediates 3, 4, 21 and 22a-g on nor-epinephrine induced contracture in thoracic rat aortic rings was investigated using prazocin as reference drug. Several derivatives showed promising activities either equal or even better than that of prazocin (IC(50) 0.487 mM). The most prospective compounds; the pyrimidinylamino coumarin derivatives 8, 17 (IC(50) 0.411, IC(50) 0.421 mM) and the chalcones 22b, 22e (IC(50) 0.371, 0.374 mM) that displayed the highest activity can be a base for lead optimization and simple but efficient design of new compounds. 2D-QSAR analysis was applied to find a correlation between the experimental vasorelaxant activities of the newly synthesized coumarin derivatives and their different physicochemical parameters. The result of this study showed that the increase in aqueous solubility while retaining good hydrophobic character of the overall molecule is the key for maintaining high relaxation activity.

Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2-one derivatives toward hepatocellular carcinoma HepG2 cells.

Based on the reported anticancer activity of coumarin and pyrazoline derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted pyrazoline moieties 7-10. The non-cyclic isosteres 11a-e of compounds 10a-e were synthesized for comparative reasons. The target compounds were synthesized from 8-acetyl-7-methoxycoumarin that underwent Claisen-Schmidt condensation with various aldehydes to give the chalcones 6a-e, followed by reaction with hydrazine hydrate, phenyl hydrazine or semicarbazide under the appropriate conditions. Cytotoxicity of the synthesized compounds was evaluated in vitro against liver HepG2 cell line. Compounds were active in the nanomolar range. The most active compounds were investigated for their telomerase inhibition and proapoptotic activities.

Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity

Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment.

Synthesis and Anticonvulsant Activity of Substituted‐1,3‐diazaspiro[4.5]decan‐4‐ones

A series of novel spiroimidazolidinone derivatives 6a–d and 8a–x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5‐ and 83.6‐fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test.

Small Molecule Inhibitors of West Nile Virus

West Nile virus (WNV) is a human pathogen which is rapidly expanding worldwide. It is a member of the Flavivirus genus and it is transmitted by mosquitos between its avian hosts and occasionally in mammalian hosts. In humans the infection is often asymptomatic, however, the most severe cases result in encephalitis or meningitis. Approximately 10% of cases of neuroinvasive disease are fatal. To date there is no effective human vaccine or effective antiviral therapy available to treat WNV infections. For this reason, research in this field is rapidly growing. In this article we will review the latest efforts in the design and development of novel WNV inhibitors from a medicinal chemistry point of view, highlighting challenges and opportunities for the researchers working in this field.

Enantioseparation of Substituted 1, 3-Diazaspiro [4.5]Decan-4-Ones: HPLC Comparative Study on Different Polysaccharide Type Chiral Stationary Phases

Enantioseparation of substituted 1,3-diazaspiro[4.5]decan-4-ones (1-14) was achieved using different polysaccharide type chiral stationary phases (CSPs), namely, Chiralcel OJ, Chiralcel OD and Lux-Amylose-2 using different mobile phases which were either n-hexane/2-propanol or n-hexane/ethanol mixtures of various ratios (v/v) at flow rate 1 mL min-1. UV detection was carried out at 254 nm and temperature of 20°C. The retention behavior and selectivity of these CSPs were examined in isocratic normal phase high-performance liquid chromatography mode. The results revealed that the amylose CSP (Lux-Amylose-2) could separate almost all the compounds under investigation in contrast to cellulose CSPs (Chiracel OJ and Chiracel OD) which resolved fewer compounds.

Design, synthesis and molecular modeling study for some new 2-substituted benzimidazoles as dual inhibitors for VEGFR-2 and c-Met

AIM Computer-aided drug design techniques were adopted to design three series of 2-substituted-5-nitrobenzimidazole derivatives hybridized with piperzine 5a,b, oxadiazole 7a,b, 9, 14a-c and triazolo-thiadiazole moieties 12a-d, as VEGFR-2/c-Met kinase inhibitors. MATERIALS & METHODS The designed compounds were synthesized adopting the chemical pathways outlined in schemes 1 and 2 to afford the desired three series followed by evaluating their inhibitory activities against VEGFR-2 and c-Met and in vitro anticancer activities. RESULT Analogs bearing substituted phenyl ring attached to oxadiazole ring 14a showed the greatest inhibitory activities against non-small-cell lung cancer NCI-H522 and melanoma SK-MEL-2 with inhibition percent of 48.70 and 42.62, respectively. Moreover, unsubstituted phenoxymethyl derivative 12d exhibited promising inhibitory activity against VEGFR-2 and c-Met (35.88 and 88.48%), respectively. CONCLUSION The above results revealed that 2-substituted-5-nitrobenzimidazole hybridized with various heterocyclic scaffolds could be a potential anticancer agent.

Synthesis, antitumor activity evaluation, and DNA-binding study of coumarin-based agents

A novel series of coumarin‐thiadiazole heterocycle derivatives was synthesized by the nucleophilic substitution reaction. The synthesized compounds were structurally verified by IR, 1H NMR, 13C NMR, mass spectra, and elemental analyses. The antitumor activity of the synthesized compounds was evaluated through DNA binding assays and the 60‐cell line panel according to the US NCI‐DTP protocol or a selection of human tumor cell lines: breast cancer (MCF‐7), liver cancer (HepG‐2), and colorectal cancer (HCT‐116). Most of the compounds had better DNA/ethidium bromide fluorescence quenching rather than methyl green displacement, suggesting superior DNA intercalation over DNA groove binding. Compounds 8 and 14b showed the best quenching effect with KSV = 4.27 × 105 M−1. Moreover, the results for compounds 8, 4c, and 4e revealed a possible dual DNA binding mode with the intercalation to be superior, with KSV 4.27 × 105, 3.96 × 105, and 3.51 × 105 M−1, respectively, compared to 42%, 45%, and 43% methyl green displacement, respectively. Out of the 60‐cell line panel, the leukemia HL‐60 cell line was the most susceptible to growth inhibition when treated with 14a, resulting in 61% growth, followed by the lung carcinoma cell line NCI‐H522 showing 67% growth when treated with 9. Moreover, compound 10c had an IC50 value of 24.9 μg/mL against the HepG‐2 cell line.