Inhibitors of Alzheimer’s BACE-1 with 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structure

Ramin Miri,Omidreza Firuzi,Nima Razzaghi-Asl,Katayoun Javidnia,Najmeh Edraki 대한약학회 2015 Archives of Pharmacal Research Vol.38 No.4

b-site amyloid precursor protein cleavingenzyme (BACE-1) is a validated target for Alzheimer therapydue to its distinctive role in pathogenesis of AD. In thepresent contribution, a series of new 3,5-bis-N-(aryl/heteroaryl)carbamoyl-4-aryl-1,4-dihydropyridine structureswere synthesized as BACE-1 inhibitors (6a–6n). In vitroBACE-1 inhibitory activities were determined by enzymaticfluorescence resonance energy transfer assay. Synthesizeddihydropyridine (DHP) analogues exhibited weak to goodinhibitory activities while 6i, 6n and 6a were found to be themost potent molecules with 83.76, 79.45 and 72.47 %BACE-1 inhibition at 10 lM, respectively. Structure binding/activity relationship elucidations revealed that superiorBACE-1 inhibitory activities were observed for DHPderivatives bearing fused/non-fused thiazole groups andparticularly 3,5-bis-N-(6-ethoxy-2-benzothiazolyl) moiety. Binding maps showed that enhanced activity may beattributed to the additional H-bond and hydrophobic interactionswith S2–S3 subpockets of BACE-1.

Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives

Hasti Sarkarzadeh,Ramin Miri,Omidreza Firuzi,Mohsen Amini,Nima Razzaghi-Asl,Najmeh Edraki,Abbas Shafiee 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.4

A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesizedand evaluated for their antiproliferative effects on HeLa,LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferativeeffects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferativeactivity in evaluated cell lines. Prepared compoundswere more potent in Jurkat cell line when compared toLS180, HeLa and MCF-7 cell lines. Compounds 29(IC16 = 0.7 lM) and 31 (IC16 = 1.7 lM) and 33 (IC16 =1.7 lM) were found to be the most potent molecules onJurkat cell lines. Moreover; it was found that some of thetested compounds bearing imidazole-2-yl moiety on theC11-position of dihydropyridine ring exhibited superiorantiproliferative activity in comparison to cis-platin especiallyin Jurkat cell line (compounds 29, 31, and 33). Itseemed that the introduction of electron-withdrawinggroups on the imidazole ring enhanced the antiproliferativepotential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazolesubstituted indeno[1,2-b]quinoline-9,11-dione compoundsmay act as efficient anticancer agents in vitro,emphasizing their potential role as a source for rationaldesign of potent antiproliferative agents.

Smell Identification Function in Children with Attention Deficit Hyperactivity Disorder

Ahmad Ghanizadeh,Maryam Bahrani,Ramin Miri,Ali Sahraian 대한신경정신의학회 2012 PSYCHIATRY INVESTIGATION Vol.9 No.2

Objective Deficits in olfactory function are common features in neurodegenerative and neuropsychiatric disorders. Olfactory processing is related to dopamine metabolism and orbitofrontal cortex functioning, both known to be involved in the neurobiology of ADHD. Some investigations suggested alterations in olfactory processing (identification and detection threshold) in patients with ADHD. Despite increasing knowledge, controversy about this topic still exists regarding children with ADHD. This study was conducted to help elucidate some of this controversy. Methods 50 participants (8-15 years, mean=10.70±1.77) with ADHD were compared to 50 controls. The two groups were well matched for age, gender and Mean School Scores (MSS). We assessed odor identification and threshold through a smell test composed of two tests of identification and detection threshold. Odor detection threshold was assessed with the odorant phenyl ethyl alcohol solved in propylene glycol using a single staircase method. Odor identification was assessed with chemical essences of five common odorants. Results The mean Sensory Identification Score for children with ADHD and the control groups were 3.76 (1.06) and 4.46 (0.76), respectively (p<0.001). The mean for Sensory Threshold Score for ADHD and control group was 6.4 (3.35) and 9.75 (2.16), respectively (p<0.001). ConclusionaaThis study replicated altered olfactory performance in ADHD. Substantial olfactory deficits across the two domains of identification and detection threshold are observed in children with ADHD. These deficits do not seem to be a result of olfactory task difficulty and are not influenced by age, gender and MSS. Further studies are required to investigate whether olfactory function can be used as a biological marker for early diagnosis, treatment and prognosis of ADHD. Objective Deficits in olfactory function are common features in neurodegenerative and neuropsychiatric disorders. Olfactory processing is related to dopamine metabolism and orbitofrontal cortex functioning, both known to be involved in the neurobiology of ADHD. Some investigations suggested alterations in olfactory processing (identification and detection threshold) in patients with ADHD. Despite increasing knowledge, controversy about this topic still exists regarding children with ADHD. This study was conducted to help elucidate some of this controversy. Methods 50 participants (8-15 years, mean=10.70±1.77) with ADHD were compared to 50 controls. The two groups were well matched for age, gender and Mean School Scores (MSS). We assessed odor identification and threshold through a smell test composed of two tests of identification and detection threshold. Odor detection threshold was assessed with the odorant phenyl ethyl alcohol solved in propylene glycol using a single staircase method. Odor identification was assessed with chemical essences of five common odorants. Results The mean Sensory Identification Score for children with ADHD and the control groups were 3.76 (1.06) and 4.46 (0.76), respectively (p<0.001). The mean for Sensory Threshold Score for ADHD and control group was 6.4 (3.35) and 9.75 (2.16), respectively (p<0.001). ConclusionaaThis study replicated altered olfactory performance in ADHD. Substantial olfactory deficits across the two domains of identification and detection threshold are observed in children with ADHD. These deficits do not seem to be a result of olfactory task difficulty and are not influenced by age, gender and MSS. Further studies are required to investigate whether olfactory function can be used as a biological marker for early diagnosis, treatment and prognosis of ADHD.

Reversal of multidrug resistance in cancer cells by novel asymmetrical 1,4-dihydropyridines

Omidreza Firuzi,Katayoun Javidnia,Elham Mansourabadi,Luciano Saso,Ahmad Reza Mehdipour,Ramin Miri 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.11

Multidrug resistance (MDR) is an importantobstacle that limits the efficacy of chemotherapy in manytypes of cancer. In this study, 14 novel asymmetrical DHPspossessing pyridyl alkyl carboxylate substitutions at C3 andalkyl carboxylate groups at C5 in addition to a nitroimidazoleor nitrophenyl moiety at C4 position were synthesized. Calciumchannel blocking (CCB) activity was measured inguinea pig ileal longitudinal smooth muscle. Cytotoxicitywas tested on 4 human cancer cell lines, while MDR reversalcapacity was examined on P-glycoprotein overexpressingdoxorubicin resistant MES-SA-DX5 and compared withnon-resistant MES-SA cells. Compounds showed differentCCB (IC50: 29.3 nM–4.75 lM) and cytotoxic activities(IC50: 6.4 to more than 100 lM). Several compounds havingnitrophenyl moiety at C4, could significantly reverse resistanceto doxorubicin at 0.5 and 1 lM. The most active oneswere 7e and 7g containing ethyl carboxylate and isopropylcarboxylate at C5, respectively. CCB activity, which isconsidered an undesirable effect for these agents, of 7e and7g were 33 and 20 times lower than nifedipine, respectively. In conclusion, the newly synthesized asymmetrical DHPcompounds showed promising MDR reversal and antitumoralactivities with low CCB effects and could be of therapeuticvalue in drug resistant cancer.