Investigation on the effect of alkyl chain linked mono-thioureas as Jack bean urease inhibitors, SAR, pharmacokinetics ADMET parameters and molecular docking studies

Larik, Fayaz Ali,Faisal, Muhammad,Saeed, Aamer,Channar, Pervaiz Ali,Korabecny, Jan,Jabeen, Farukh,Mahar, Ihsan Ali,Kazi, Mehar Ali,Abbas, Qamar,Murtaza, Ghulam,Khan, Gul Shahzada,Hassan, Mubashir,Seo, Academic Press 2019 Bioorganic chemistry Vol.86 No.-

<P><B>Abstract</B></P> <P>The increasing resistance of pathogens to common antibiotics, as well as the need to control urease activity to improve the yield of soil nitrogen fertilization in agricultural applications, has stimulated the development of novel classes of molecules that target urease as an enzyme. In this context, the newly developed compounds on the basis of 1-heptanoyl-3-arylthiourea family were evaluated for Jack bean urease enzyme inhibition activity to validate their role as potent inhibitors of this enzyme. 1-Heptanoyl-3-arylthioureas were obtained in excellent yield and characterized through spectral and elemental analysis. All the compounds displayed remarkable potency against urease inhibition as compared to thiourea standard. It was found that novel compounds fulfill the criteria of drug-likeness by obeying Lipinski’s rule of five. Particularly compound <B>4a</B> and <B>4c</B> can serve as lead molecules in 4D (drug designing discovery and development). Kinetic mechanism and molecular docking studies also carried out to delineate the mode of inhibition and binding affinity of the molecules.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A new family of 1-heptanoyl-3-arylthioureas (<B>4a-4j</B>) was synthesized in excellent yield. </LI> <LI> The synthesized 1-heptanoyl-3-arylthiourea family were evaluated for Jack bean urease enzyme inhibition activity. </LI> <LI> Particularly compound <B>4a</B> and <B>4c</B> can serve as lead molecules in 4D (drug designing discovery and development). </LI> <LI> Kinetic mechanism and molecular docking studies also carried out to delineate the mode of inhibition and binding affinity. </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>

CONSTRUCTION AND INITIALIZATION OF A HIDDEN LAYER OF MULTILAYER NEURAL NETWORKS FOR PATTERN CLASSIFICATION

Kim, Larik Sang 淸州大學校 産業經營硏究所 1996 産業經營硏究 Vol.19 No.2

A novel approach for constructing and initializing a hidden layer of multilayer neural networks for pattern classification is presented. The proposed method forms hidden layer by clustering and initializing weights of hidden units using linear programming so that the back-propagation algorithm can start with linear hyperplanes around input patterns rather than the whole input space. Experimental results show that the method generates the hidden layer much more efficiently and train the net faster than the ordinary back-propagation method.

Beijing’s cultural diplomacy efforts in Pakistan: Building soft image through internet sources

Abdul Razaque Larik,Shah Nawaz Mangi,Syed Gulzar Ali Shah Bukhari 한국국제정치학회 2022 The Korean Journal of International Studies Vol.20 No.3

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>

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>

Risk of Breast Cancer among Young Women and Importance of Early Screening

Memon, Zahid Ali,Kanwal, Noureen,Sami, Munam,Larik, Parsa Azam,Farooq, Mohammad Zain Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.17

Background: Breast cancer is the most common type of cancer in women throughout the world. However, in comparison with Western women, it presents relatively early in women of Asian ethnicity. Early menarche, late menopause, use of OCP's, family history of benign or malignant breast disease, exposure to radiation and BMI in the under-weight range are well known risk factors for the development of breast cancer in premenopausal women. Early detection with the use of breast self-examination (BSE) and breast cancer screening programs can lead to a reduction in the mortality rates due to breast cancer. The aim of our study was to assess the risk factors for breast cancer among young women and to emphasize the importance of early screening among them. Materials and Methods: We conducted a cross-sectional study among women aged 18 to 25 using a self-administered questionnaire. Data was collected over a period of 6 months from June to December, 2014. A total of 300 young women selected randomly from Dow Medical College and various departments of Karachi University successfully completed the survey. Results: Respondents were 18-25 years of age (mean age=21.5). Out of the 300 young females, 90 (30%) had at least one risk factor, 90 (30%) had two, 40 (13%) had three, 8 (2.7%) had four, 2 (0.7%) had five while one female was found to have six positive risk factors for breast cancer. Some 66 women (22%) experienced symptoms of breast cancer such as non-cyclical pain and lumps. While 222 women (74%) had never performed breast self-examination, 22 (7.3%) had had a breast examination done by a health professional while 32 (10.7%) had participated in breast screening programs. A total of 223 (74.3%) women considered breast cancer screening important for young women. Conclusions: The percentage of young women with risk factors for breast cancer was found to be alarmingly high. Therefore, screening for breast cancer should start at an early age especially in high risk groups. Awareness about breast self-examination should be emphasized. Moreover, screening programs should be started to ensure early detection and reduction of mortality rates caused by breast cancer also in young Pakistani females.

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>

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>

Synthesis, molecular docking studies of coumarinyl-pyrazolinyl substituted thiazoles as non-competitive inhibitors of mushroom tyrosinase

Saeed, A.,Mahesar, P.A.,Channar, P.A.,Abbas, Q.,Larik, F.A.,Hassan, M.,Raza, H.,Seo, S.Y. Academic Press 2017 Bioorganic chemistry Vol.74 No.-

A series of coumarinyl-pyrazolinyl substituted thiazoles derivatives were synthesized and their inhibitory effects on the DPPH and mushroom tyrosinase were evaluated. The results showed that all of the synthesized compounds exhibited significant mushroom tyrosinase inhibitory activities. In particular, 3-(5-(4-(benzyloxy)-3-methoxyphenyl)-1-(4-(4-bromophenyl)thiazol-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (7j) exhibited the most potent tyrosinase inhibitory activity with IC<SUB>50</SUB> value 0.00458+/-0.00022μM compared with the IC<SUB>50</SUB> value of kojic acid is 16.84+/-0.052μM. The inhibition mechanism analyzed by Lineweaver-Burk plots revealed that the type of inhibition of compound 7j on tyrosinase was noncompetitive. The docking study against tyrosinase enzyme was also performed to determine the binding affinity of the compounds. The compound 7a showed the highest binding affinity (-10.20kcal/mol) with active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that compound 7j may serve asa structural template for the design and development of novel tyrosinase inhibitors.