Nasser S.M. Ismail

Design, synthesis and biological study of novel pyrido(2,3-d)pyrimidine as anti-proliferative CDK2 inhibitors

The design and synthesis of a small library of 4-aminopyrido[2,3-d]pyrimidine derivatives is reported. The potential activity of these compounds as CDK2/Cyclin A, CDK4/Cyclin D, EGFR and anti-tumor was evaluated by cytotoxicity studies in A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme activity in vitro. The anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds 4c and 11a was significantly more active than roscovotine with IC(50) 0.3 and 0.09 μM respectively. Molecular modeling study, including fitting to a 3D-pharmacophore model, docking into cyclin dependant kinase2 (CDK2) active site and binding energy calculations were carried out and these studies suggested the same binding orientation inside the CDK2 binding pocket for these analogs compared to ATP.

Discovery of Novel Benzo[a]phenoxazine SSJ-183 as a Drug Candidate for Malaria

Malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. Even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. Novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. A search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. The derivative SSJ-183 (5), having a 4-aminopyridine group, showed an IC50 value against Plasmodium falciparum of 7.6 nM and a selectivity index of >7300. Cure was achieved by three oral doses of 5 at 100 mg/kg to mice infected with the Plasmodium berghei ANKA strain. The safety of 5 was supported by acute toxicity testing in mice with single doses up to 2000 mg/kg po, chromosome aberration test, in vitro as well as in vivo micronucleus tests, and phototoxicity studies in mice. Thus, 5 is a promising candidate as a new antimalarial agent.

Synthesis, hypnotic properties and molecular modeling studies of 1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones.

1,3-Dipolar cycloaddition reaction of nitrilimines with 5-arylidene-1,3-dimethyl-2,4,6-pyrimidinetriones 1a-i afforded 7,9-dimethyl-1,3,4-triaryl-1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones 3a-k in a high regioselective manner. Single crystal X-ray study of 3d added a conclusive support for the assigned structure. Potentiating effects of the synthesized compounds 3a-k (at a dose of 25 mg/kg body weight) on hypnotic action of sodium thiopental (at a dose of 75 mg/kg body weight i.p.) were investigated in vivo using Albino mice according to the standard method. Most of the tested compounds revealed promising hypnotic potentiating effects especially compounds 3k and 3e that could be nominated as short-acting hypnotics. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into optimized homology model of GABA(A)-α(1) showed good results consistent with the observed pharmacological properties.

Facile synthesis, vasorelaxant properties and molecular modeling studies of 2-amino-8a-methoxy-4H-pyrano[3,2-c]pyridine-3-carbonitriles

A facile synthetic approach towards 6-alkyl-2-amino-4-aryl-4a,5,6,7,8,8a-hexahydro-8a-methoxy-4H-pyrano[3,2-c]pyridine-3-carbonitriles 3a-n was reported via reaction of 1-alkyl-4-piperidones 1a,b with ylidenemalononitriles 2a-h in methanol in the presence of sufficient amount of sodium. The structure of 3 was established through different spectroscopic techniques and confirmed by single crystal X-ray studies. Vasodilation activities of the synthesized compounds were investigated in vitro using isolated thoracic aortic rings of Wister rats pre-contracted with norepinephrine hydrochloride standard method. All the prepared analogues exhibited considerable vasodilation properties especially, 3g and 3c which revealed the best vasodilation potency (IC50=0.30, 0.37 mM, respectively) among all the tested compounds. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α1-AR antagonists showed high docking score and fit values. The experimental vasodilation activities of compounds 3a-n are consistent with their molecular modeling results.

Computer based design, synthesis and biological evaluation of novel indole derivatives as HCV NS3-4A serine protease inhibitors

A series of novel indoles were designed and their molecular modeling simulation study including fitting to a 3D pharmacophore model using CATALYST program and their docking into the NS3 active site was examined as HCV NS3 protease inhibitor. Several compounds showed significant high simulation docking score and fit values. The designed compounds were synthesized and biologically evaluated in vitro using an NS3 protease binding assay, where compounds 10a-k showed significant inhibitory activity (> or =67% inhibition at 100 microg/mL). Of these, compounds 10c and 10f demonstrated potent HCV NS3 protease inhibitors with IC(50) values of 15 and 13 microM, respectively. Enantio-selective Michael addition of an indole derivative in the presence of catalytic amount of AlCl(3) and quinine at room temperature afforded the adduct 7e in excellent yield with 73% ee. The product was converted into 10l, which showed lower activity than the mixture of the corresponding diastereoisomers.

A convenient synthesis and molecular modeling study of novel purine and pyrimidine derivatives as CDK2/cyclin A3 inhibitors

A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their in vitro anti-CDK2/cyclin A3 and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay. The novel purine derivatives 13a,b demonstrated potent inhibitor activities with IC(50) values of 14±9 and 13±9 μM, respectively. Additionally, compound 15a showed the highest potency (IC(50)=10±6 μM) in EAC cell based assay. Molecular modeling study, including fitting to a 3D-pharmacophore model and their docking into cyclin dependant kinase2 (CDK2) active site showed high fit values and docking scores.

ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents

A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.

Quinoxaline-Based Scaffolds Targeting Tyrosine Kinases and Their Potential Anticancer Activity

Quinoxaline derivatives, also called benzopyrazines, are an important class of heterocyclic compounds. Quinoxalines have drawn great attention due to their wide spectrum of biological activities. They are considered as an important basis for anticancer drugs due to their potential activity as protein kinase inhibitors. In this review, we focus on the chemistry of the quinoxaline derivatives, the strategies for their synthesis, their potential activities against various tyrosine kinases, and on the structure–activity relationship studies reported to date.

Design, synthesis and biological evaluation of type-II VEGFR-2 inhibitors based on quinoxaline scaffold.

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a series of new quinoxaline-based derivatives was designed and synthesized. The target compounds were biologically evaluated for their inhibitory activity against VEGFR-2. The design of the target compounds was accomplished after a profound study of the structure activity relationship (SAR) of type-II VEGFR-2 inhibitors. Among the synthesized compounds, 1-(2-((4-methoxyphenyl)amino)-3-oxo-3,4 dihydroquinoxalin-6-yl)-3-phenylurea (VIIa) displayed the highest inhibitory activity against VEGFR-2. Molecular modeling study involving molecular docking and field alignment was implemented to interpret the variable inhibitory activity of the newly synthesized compounds.

Molecular modeling based approach, synthesis and in vitro assay to new indole inhibitors of hepatitis C NS3/4A serine protease

In an attempt to identify potential HCV NS3 protease inhibitors lead compounds, a series of novel indoles (10a-g) was designed. Molecular modeling study, including fitting to a 3D-pharmacophore model of the designed molecules (10a-g), with HCV NS3 protease hypothesis using catalyst program was fulfilled. Also, the molecular docking into the NS3 active site was examined using Discovery Studio 2.5 software. Several compounds showed significant high simulation docking score and fit values. The designed compounds with high docking score and fit values were synthesized and biologically evaluated in vitro using an NS3 protease binding assay. It appears that most of the tested compounds reveal promising inhibitory activity against NS3 protease. Of these, compounds 10a and 10b demonstrated potent HCV NS3 protease inhibitors with IC(50) values of 9 and 12μg/mL, respectively. The experimental serine protease inhibitor activities of compounds 10a-g were consistent with their molecular modeling results. Inhibitors from this class have promising characteristics for further development as anti-HCV agents.