Synthesis of 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyridines as novel skin protecting and anti-aging agents

Saeed, Aamer,Shahzad, Danish,Larik, Fayaz Ali,Channar, Pervaiz Ali,Mahfooz, Haroon,Abbas, Qamar,Hassan, Mubashir,Raza, Hussain,Seo, Sung-Yum,Shabir, Ghulam Bangladesh Journals Online 2017 Bangladesh journal of pharmacology Vol.12 No.2

<P><p>A series of 4-aryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyri-dines 6a-6h were prepared by using the one-pot three component synthetic method. The target compounds 6a-6h were synthesized by reacting two molar equivalents of ketone functionality and one mole of aromatic aldehydes in ammonium acetate to obtain the desired products. The structures of newly synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. All the synthesized compounds were screened for their elastase inhibition and antioxidant activity. Almost all of the com-pounds 6a-h showed good to excellent activities against elastase enzyme more than the reference drug. Compounds 6d and 6b at 0.2 ± 0.0 µM and 0.2 ± 0.0 µM were found to most potent derivatives against elastase enzyme. Compound 6a exhibited prominent free radical scavenging activity. From the results of the biological activity, we infer that some derivatives can serve as lead molecules in pharmacology.</p><p><strong>Video Clip of Methodology</strong>:</p><p>3 min 13 sec <a href='https://youtube.com/v/gPLdpGpZhR8'>Full Screen</a> <a href='https://youtube.com/watch?v=gPLdpGpZhR8'>Alternate</a></p></P>

Synthesis and enzyme inhibitory kinetics of some novel 3-(substituted benzoyl)-2-thioxoimidazolidin-4-one derivatives as α-glucosidase/α-amylase inhibitors

Qamar, Rabia,Saeed, Aamer,Saeed, Maria,Shah, Babar Hussain,Ashraf, Zaman,Abbas, Qamar,Seo, Sung Yum Springer-Verlag 2018 Medicinal Chemistry Research Vol.27 No.5

Synthesis and Biological Evaluation of 3‐thiazolocoumarinyl Schiff‐base Derivatives as Cholinesterase Inhibitors

Raza, Rabia,Saeed, Aamer,Arif, Mubeen,Mahmood, Shamsul,Muddassar, Muhammad,Raza, Ahsan,Iqbal, Jamshed Blackwell Publishing Ltd 2012 Chemical biology & drug design Vol.80 No.4

<P>On the basis of the observed biological activity of the coumarins, a new set of 3‐thiazolocoumarinyl Schiff‐base derivatives with chlorine, hydroxy and methoxy functional group substitutions were designed and synthesized. These compounds were tested against acetylcholinesterase from <I>Electrophorus electricus</I> and butyrylcholinesterase from horse serum and their structure–activity relationship was established. Studies revealed them as the potential inhibitors of cholinesterase (acetylcholinesterase and butyrylcholinesterase). The <B>3f</B> was found to be most potent against acetylcholinesterase with <I>K</I><SUB>i</SUB> value of 1.05 ± 0.3 μ<SMALL>m</SMALL> and <B>3l</B> showed excellent inhibitory action against butyrylcholinesterase with <I>K</I><SUB>i</SUB> value of 0.041 ± 0.002 μ<SMALL>m</SMALL>. The synthesized compounds were also docked into the active sites of the homology models of acetylcholinesterase and butyrylcholinesterase to predict the binding modes of these compounds. It was predicted that most of the compounds have similar binding modes with reasonable binding affinities. Our docking studies have also shown that these synthesized compounds have better interaction patterns with butyrylcholinesterase over acetylcholinesterase. The main objective of the study was to develop new potent and selective compounds, which might be further optimized to prevent the progression of the Alzheimer’s disease and could provide symptomatic treatment.</P>

Journey of the ALK-inhibitor CH5424802 to phase II clinical trial

Muhammad Latif,Aamer Saeed,김성환 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.9

The anaplastic lymphoma kinase (ALK) receptortyrosine kinase represents a potential therapeutic target. Specially, a variety of alterations in the ALK geneincluding mutations, overexpression, amplification, translocationsand structural rearrangements, are involved inhuman cancer tumorigenesis. The second-generation ALKinhibitor CH5424802 (development code: AF802; ChugaiPharmaceutical, a subsidiary of Roche) achieves tumorregression with excellent tolerance and shows promisingefficacy in patients with ALK-positive non-small cell lungcancer. CH5424802 shows good kinase selectivity, has apromising pharmacokinetics profile, and has strong antiproliferativeactivity in several ALK-driven tumor models. CH5424802 has also shown anti-tumor activity in mousexenograft studies. Here, we summarize recent advances andthe evidence that CH5424802 acts as an ALK inhibitor. We also discuss its potential for further development as ananticancer drug in clinical trials.

1-(2-Hydroxy-5-((trimethylsilyl)ethynyl)phenyl)ethanone based α,β-unsaturated derivatives an alternate to non-sulfonamide carbonic anhydrase II inhibitors, synthesis via Sonogashira coupling, binding analysis, Lipinsk’s rule validation

Mahar, Jamaluddin,Saeed, Aamer,Belfield, Kevin D.,Ali Larik, Fayaz,Ali Channar, Pervaiz,Ali Kazi, Mehar,Abbas, Qamar,Hassan, Mubashir,Raza, Hussain,Seo, Sung-Yum Elsevier 2019 Bioorganic chemistry Vol.84 No.-

<P><B>Abstract</B></P> <P>A novel series of silyl-yne containing chalcone derivatives <B>5a-5j</B> was synthesized by exploiting Sonogashira coupling reaction and Claisen-Schimdt condensation reaction. The synthesized derivative were characterized by spectroscopic and elemental analysis. The selective inhibition of carbonic anhydrases is considered critical in the field of medicinal chemistry because carbonic anhydrases exits in several isoforms. Synthesized compounds were subjected to carbonic anhydrase –II assay. Except <B>5j</B>, the other derivatives exhibited better potential than standard acetazolamide. Compound <B>5e</B> was found to be potent derivative in the series with IC<SUB>50</SUB> value 0.054 ± 0.001 µM. Binding analysis revealed that most potent derivative 5e binds in the active site of CA-II and single π-π stacking interaction was observed between ring structure of ligand and Phe129 having bond length 4.90 Å. Pharmacokinetics elicited that compounds obey Lipinski’s rule and show significant drug score.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Sonogashira coupling reaction was used to synthesized novel silicon containing alkyne compounds. </LI> <LI> Synthesized compounds were evaluated against carbonic anhydrase II enzyme. </LI> <LI> Binding analysis and pharmacokinetics was explored. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Synthesis of sulfadiazinyl acyl/aryl thiourea derivatives as calf intestinal alkaline phosphatase inhibitors, pharmacokinetic properties, lead optimization, Lineweaver-Burk plot evaluation and binding analysis

Sajid-ur-Rehman,Saeed, Aamer,Saddique, Gufran,Ali Channar, Pervaiz,Ali Larik, Fayaz,Abbas, Qamar,Hassan, Mubashir,Raza, Hussain,Fattah, Tanzeela Abdul,Seo, Sung-Yum Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.12

<P><B>Abstract</B></P> <P>To seek the new medicinal potential of sulfadiazine drug, the free amino group of sulfadiazine was exploited to obtain acyl/aryl thioureas using simple and straightforward protocol. Acyl/aryl thioureas are well recognized bioactive pharmacophore containing moieties. A new series (<B>4a</B>–<B>4j</B>) of sulfadiazine derived acyl/aryl thioureas was synthesized and characterized through spectroscopic and elemental analysis. The synthesized derivatives <B>4a</B>–<B>4j</B> were subjected to calf intestinal alkaline phosphatase (CIAP) activity. The derivative <B>4a</B>–<B>4j</B> showed better inhibition potential compared to standard monopotassium phosphate (MKP). The compound <B>4c</B> exhibited higher potential in the series with IC<SUB>50</SUB> 0.251 ± 0.012 µM (standard KH<SUB>2</SUB>PO<SUB>4</SUB> 4.317 ± 0.201 µM). Lineweaver-Burk plots revealed that most potent derivative <B>4c</B> inhibition CIAP via mixed type pathway. Pharmacological investigations showed that synthesized compounds <B>4a</B>–<B>4j</B> obey Lipinsk’s rule. ADMET parameters evaluation predicted that these molecule show significant lead like properties with minimum possible toxicity and can serve as templates in drug designing. The synthetic compounds show none mutagenic and irritant behavior. Molecular docking analysis showed that compound <B>4c</B> interacts with Asp273, His317 and Arg166 amino acid residues.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Sulfadiazine based acyl/aryl thioureas has been synthesized and were screen against calf intestinal alkaline phosphatase (CIAP). </LI> <LI> Compound <B>4c</B> was found to be potent derivative in the series. </LI> <LI> Lineweaver-Burk plots revealed mixed type of enzyme inhibition mechanism. </LI> <LI> All the derivatives <B>4a</B>–<B>4j</B> obey Lipinski’s Rule. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Design, synthesis, kinetic mechanism and molecular docking studies of novel 1-pentanoyl-3-arylthioureas as inhibitors of mushroom tyrosinase and free radical scavengers

Larik, Fayaz Ali,Saeed, Aamer,Channar, Pervaiz Ali,Muqadar, Urooj,Abbas, Qamar,Hassan, Mubashir,Seo, Sung-Yum,Bolte, Michael S.E.C.T. [etc.] 2017 European journal of medicinal chemistry Vol.141 No.-

<P><B>Abstract</B></P> <P>A series of novel 1-pentanoyl-3-arylthioureas was designed as new mushroom tyrosinase inhibitors and free radical scavengers. The title compounds were obtained in excellent yield and characterized by FTIR, <SUP>1</SUP>H NMR, <SUP>13</SUP>C NMR and X-ray crystallography in case of compound (<B>4a</B>). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 1-Pentanoyl-3-(4-methoxyphenyl) thiourea (<B>4f</B>) showed tyrosinase inhibitory activity (IC<SUB>50</SUB> 1.568 ± 0.01 mM) comparable to Kojic acid (IC<SUB>50</SUB> 16.051 ± 1.27 mM). Interestingly compound <B>4f</B> exhibited higher antioxidant potential compared to other derivatives. The docking studies of synthesized 1-Pentanoyl-3-arylthioureas analogues were also carried out against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC<SUB>50</SUB> values. The predicted binding affinities are in good agreement with the IC<SUB>50</SUB> values as compound (<B>4f</B>) showed highest binding affinity (−7.50 kcal/mol) compared to others derivatives. The kinetic mechanism analyzed by Line-weavere Burk plots exhibited that compound (<B>4f</B>) inhibit the enzyme inhibits the tyrosinase non-competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (<B>4f</B>) is 1.10 μM. It was also found from kinetic analysis that derivative <B>4f</B> irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound (<B>4f</B>) may serve as lead structure for the design of more potent tyrosinase inhibitors.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A small library of novel 1-Pentanoyl-3-arylthioureas (<B>4a-4j</B>) synthesized. </LI> <LI> Mushroom tyrosinase inhibition and free radical scavenging activity were evaluated. </LI> <LI> Most of the compounds show excellent activity, particularly <B>4f</B> higher than the standard. </LI> <LI> The kinetic mechanism proposed <B>4f</B> is non-competitive inhibitor of mushroom tyrosinase. </LI> <LI> Molecular docking, druglikeness, Ramachandran graph, Chemo-informatics and Lipinski's rule were studied. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Locator Placement Optimization for Minimum Part Positioning Error During Machining Operation Using Genetic Algorithm

Sajid Ullah Butt,Mamoona Arshad,Aamer Ahmed Baqai,Hasan Aftab Saeed,Naveed Akmal Din,Rehan Ahmed Khan 한국정밀공학회 2021 International Journal of Precision Engineering and Vol.22 No.5

Fixture design is one of the main factors which affect the final product quality. Proper design of fixture plays an important role in ensuring the required tolerance of the product. Proper placement of locators is one of the prominent factors in fixture design. Locators are elastic: they deform under clamping and machining forces causing rigid body displacement of the workpiece which in turn affects the part quality. In this article, a 3-2-1 type of fixturing system having elastic locators around a considerably rigid rectangular workpiece is considered. A genetic algorithm is proposed, which uses a fitness function that evaluates the positioning error of the workpiece under external forces and torque. Among several variables, 12 variables, which define the placement of locators, are chosen to be optimized while minimizing the positioning error of the workpiece at the point of action of machining force. The proposed algorithm optimizes the 12 interlinked variables, within the specified region, for machining force and torque at a single point. However, when the cutting tool moves to any other point on the workpiece, it is observed that either the workpiece loses its contact with any one of the locators or the positioning error increases by a large value. To overcome this issue, the proposed algorithm is further modified for placement optimization to cater for multi-point machining, and the isostatism of the workpiece is ensured by checking the magnitude and direction of displacement (of what?) at each point of workpiece-locator contact. Finally, the original and modified GA algorithms are explained through a case study where the single point optimized placement shows loss of contact when machining force is applied at other points. The placement optimized from the modified algorithm shows that the isostatism of the workpiece remains intact while all four positioning errors are converged towards the same value. The results obtained from the proposed and modified algorithm are verified using ANSYS simulation.

One-pot four-component synthesis of thiazolidin-2-imines using Cu^I/Zn^II dual catalysis: A new class of acetylcholinesterase inhibitors

Shehzadi, Syeda Aaliya,Khan, Imtiaz,Saeed, Aamer,Larik, Fayaz Ali,Channar, Pervaiz Ali,Hassan, Mubashir,Raza, Hussain,Abbas, Qamar,Seo, Sung-Yum Academic Press 2019 Bioorganic chemistry Vol.84 No.-

<P><B>Abstract</B></P> <P>An efficient one-pot four-component strategy involving aldehydes, amines, alkynes and isothiocyanates has been developed to access a novel series of thiazolidine-2-imines (<B>5a-x</B>). This process operates under the action of a cooperative catalysis composed of Cu(I) and Zn(II) delivering the desired five-membered heterocyclic compounds in good to excellent yields. Notably, this transformation avoids the use of pre-formed imines or propargylamines and proceeds <I>via</I> an intramolecular 5-<I>exo-dig</I> hydrothiolation reaction of the <I>in situ</I> formed propargyl thiourea. Furthermore, the biological application of these motifs was demonstrated in terms of their strong acetylcholinesterase (AChE) inhibitory activity where compound <B>5s</B> was identified as the lead AChE inhibitor with an IC<SUB>50</SUB> value of 0.0023 ± 0.0002 μM, 88-folds stronger inhibition than standard drug (neostigmine methyl sulphate; IC<SUB>50</SUB> = 0.203 ± 0.004 μM). Molecular docking analysis reinforced the <I>in vitro</I> biological activity results revealing the formation of several useful interactions of the potent lead with amino acid residues in the active site of the enzyme.</P> <P><B>Highlights</B></P> <P> <UL> <LI> One-pot four component methodology was developed under Cu/Zn dual catalysis. </LI> <LI> A diverse range of thiazolidin-2-imines was prepared in excellent yields. </LI> <LI> Good functional group tolerance and broad substrate scope were explored. </LI> <LI> Potent inhibitors (<B>5b</B>, <B>5i</B>, <B>5s</B>, <B>5t</B>) of acetylcholinesterase were identified. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Synthesis of sulfonamide, amide and amine hybrid pharmacophore, an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis

Ahmed, Attique,Channar, Pervaiz Ali,Saeed, Aamer,Kalesse, Markus,Kazi, Mehar Ali,Larik, Fayaz Ali,Abbas, Qamar,Hassan, Mubashir,Raza, Hussain,Seo, Sung-Yum Elsevier 2019 Bioorganic chemistry Vol.86 No.-

<P><B>Abstract</B></P> <P>Selective inhibition of carbonic anhydrase (CA) enzyme is an active area of research for medicinal chemists. In the current account, a hybrid pharmacophore approach was employed to design sulfonamide, amide and amine containing new series of potent carbonic anhydrase II inhibitors. The aromatic fragment associated with pharmacophore was altered suitably in order to find effective inhibitors of CA-II. All the derivatives <B>4a-4m</B> showed better inhibition compared to the standard acetazolamide. In particular, compound <B>4l</B> exhibited significant inhibition with IC<SUB>50</SUB> value of 0.01796 ± 0.00036 µM. The chemo-informatics analysis justified that all the designed compounds possess <10 HBA and <5 HBD. The ligands-protein binding analyses showed that <B>4l</B> confined in the active binding pocket with three hydrogen bonds observed with His63, Asn66 and Thr197 residues.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Hybrid pharmacophore containing sulfonamide, amide and amine designed and synthesized. </LI> <LI> All the derivatives <B>4a-4m</B> showed better inhibition than acetazolamide, with <B>4l</B> exhibiting momentous inhibition. </LI> <LI> The chemo-informatics and ligands-protein binding analyses carried out. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>