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Molecules
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Advancement in Design and Synthesis of Novel Drug
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Advancement in Design and Synthesis of Novel Drug

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 17499

Special Issue Editor

Dr. Manoj K. Pandey

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
Interests: multiple myeloma; drug design; leukemia, drug development; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of a novel medicine starts when researchers learn of a biological target, such as protein, gene, receptor etc., which plays a critical role in diseases such as cancers, diabetes, or neurological disorders. This Special Issue will cover the discovery and development of a variety of novel agents. Here, we will cover the discovery and development of entirely new agents, those with a mode of action different from already approved medicines and intended for clinical translations. Our aim is to publish the recent advancement in the area of drug discovery and development. One overall theme of our Special Issue is to report the preclinical or clinical studies of novel agents and understand their designing, synthesis, and characterization. This Special Issue will facilitate the translation of new agents to the next level. As editors of the journal, we encourage the submission of research reports that provide data relevant to this Special Issue.

Dr. Manoj K. Pandey
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • medicinal chemistry
  • pharmaceuticals
  • nutraceuticals
  • drug design
  • drug development
  • cancer
  • inflammations

Published Papers (6 papers)

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Research

17 pages, 2979 KiB  
Article
A Phage Display-Identified Short Peptide Capable of Hydrolyzing Calcium Pyrophosphate Crystals—The Etiological Factor of Chondrocalcinosis
by Radosław W. Piast, Rafał M. Wieczorek, Nicola Marzec, Maciej Garstka and Aleksandra Misicka
Molecules 2021, 26(19), 5777; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195777 - 24 Sep 2021
Viewed by 2191
Abstract
Chondrocalcinosis is a metabolic disease caused by the presence of calcium pyrophosphate dihydrate crystals in the synovial fluid. The goal of our endeavor was to find out whether short peptides could be used as a dissolving factor for such crystals. In order to [...] Read more.
Chondrocalcinosis is a metabolic disease caused by the presence of calcium pyrophosphate dihydrate crystals in the synovial fluid. The goal of our endeavor was to find out whether short peptides could be used as a dissolving factor for such crystals. In order to identify peptides able to dissolve crystals of calcium pyrophosphate, we screened through a random library of peptides using a phage display. The first screening was designed to select phages able to bind the acidic part of alendronic acid (pyrophosphate analog). The second was a catalytic assay in the presence of crystals. The best-performing peptides were subsequently chemically synthesized and rechecked for catalytic properties. One peptide, named R25, turned out to possess some hydrolytic activity toward crystals. Its catalysis is Mg2+-dependent and also works against soluble species of pyrophosphate. Full article
(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drug)
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13 pages, 2872 KiB  
Article
Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine, DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis
by Rabin Neupane, Saloni Malla, Mariam Sami Abou-Dahech, Swapnaa Balaji, Shikha Kumari, Digambar Kumar Waiker, N. S. Hari Narayana Moorthy, Piyush Trivedi, Charles R. Ashby, Jr., Chandrabose Karthikeyan and Amit K. Tiwari
Molecules 2021, 26(15), 4417; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26154417 - 22 Jul 2021
Cited by 3 | Viewed by 2601
Abstract
A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the [...] Read more.
A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC. Full article
(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drug)
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20 pages, 6370 KiB  
Article
A Novel Dialkylamino-Functionalized Chalcone, DML6, Inhibits Cervical Cancer Cell Proliferation, In Vitro, via Induction of Oxidative Stress, Intrinsic Apoptosis and Mitotic Catastrophe
by Jenna M. Len, Noor Hussein, Saloni Malla, Kyle Mcintosh, Rahul Patidar, Manivannan Elangovan, Karthikeyan Chandrabose, N. S. Hari Narayana Moorthy, Manoj Pandey, Dayanidhi Raman, Piyush Trivedi and Amit K. Tiwari
Molecules 2021, 26(14), 4214; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26144214 - 11 Jul 2021
Cited by 4 | Viewed by 3053
Abstract
In this study, we designed, synthesized and evaluated, in vitro, novel chalcone analogs containing dialkylamino pharmacophores in the cervical cancer cell line, OV2008. The compound, DML6 was selective and significantly decreased the proliferation of OV2008 and HeLa cells in sub-micromolar concentrations, compared to [...] Read more.
In this study, we designed, synthesized and evaluated, in vitro, novel chalcone analogs containing dialkylamino pharmacophores in the cervical cancer cell line, OV2008. The compound, DML6 was selective and significantly decreased the proliferation of OV2008 and HeLa cells in sub-micromolar concentrations, compared to prostate, lung, colon, breast or human embryonic kidney cell line (HEK293). DML6, at 5 μM, arrested the OV2008 cells in the G2 phase. Furthermore, DML6, at 5 μM, increased the levels of reactive oxygen species and induced a collapse in the mitochondrial membrane potential, compared to OV2008 cells incubated with a vehicle. DML6, at 5 μM, induced intrinsic apoptosis by significantly (1) increasing the levels of the pro-apoptotic proteins, Bak and Bax, and (2) decreasing the levels of l the anti-apoptotic protein, Bcl-2, compared to cell incubated with a vehicle. Furthermore, DML6, at 5 and 20 μM, induced the cleavage of caspase-9, followed by subsequent cleavage of the executioner caspases, caspase-3 and caspase-7, which produced OV2008 cell death. Overall, our data suggest that DML6 is an apoptosis-inducing compound that should undergo further evaluation as a potential treatment for cervical cancer. Full article
(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drug)
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13 pages, 1926 KiB  
Communication
In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in Leishmania spp.
by Juliana Figueiredo Peixoto, Adriane da Silva Oliveira, Patrícia Queiroz Monteiro, Luiz Filipe Gonçalves-Oliveira, Valter Viana Andrade-Neto, Vitor Francisco Ferreira, Franklin Souza-Silva and Carlos Roberto Alves
Molecules 2021, 26(12), 3537; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26123537 - 10 Jun 2021
Cited by 3 | Viewed by 2153
Abstract
Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the Leishmania spp. multiplication, there are gaps in the molecular binding [...] Read more.
Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the Leishmania spp. multiplication, there are gaps in the molecular binding details of target enzymes related to the parasite’s physiology. Molecular docking assays simulations were performed using DockThor server to predict the preferred orientation of both compounds to form stable complexes with key enzymes of metabolic pathway, electron transport chain, and lipids metabolism of Leishmania spp. This study showed the hit rates of both compounds interacting with lanosterol C-14 demethylase (−8.4 kcal/mol to −7.4 kcal/mol), cytochrome c (−10.2 kcal/mol to −8.8 kcal/mol), and glyceraldehyde-3-phosphate dehydrogenase (−8.5 kcal/mol to −7.5 kcal/mol) according to Leishmania spp. and assessed compounds. The set of molecular evidence reinforces the potential of both compounds as multi-target drugs for interrupt the network interactions between parasite enzymes, which can lead to a better efficacy of drugs for the treatment of leishmaniases. Full article
(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drug)
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18 pages, 16407 KiB  
Article
Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders
by Aimo Kannt, Sridharan Rajagopal, Mahanandeesha S. Hallur, Indu Swamy, Rajendra Kristam, Saravanakumar Dhakshinamoorthy, Joerg Czech, Gernot Zech, Herman Schreuder and Sven Ruf
Molecules 2021, 26(4), 991; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26040991 - 13 Feb 2021
Cited by 17 | Viewed by 3680
Abstract
Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines [...] Read more.
Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies. Full article
(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drug)
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12 pages, 1623 KiB  
Article
Synthesis, Antitumor and Antibacterial Studies of New Shortened Analogues of (KLAKLAK)2-NH2 and Their Conjugates Containing Unnatural Amino Acids
by Sirine Jaber, Ivan Iliev, Tsvetelina Angelova, Veronica Nemska, Inna Sulikovska, Emilia Naydenova, Nelly Georgieva, Ivan Givechev, Ivo Grabchev and Dancho Danalev
Molecules 2021, 26(4), 898; https://doi.org/10.3390/molecules26040898 - 08 Feb 2021
Cited by 13 | Viewed by 2565
Abstract
(1) Background: (KLAKLAK)2 is a representative of the antimicrobial peptide group which also shows good anticancer properties. (2) Methods: Herein, we report synthesis using SPPS and characterization by HPLC/MS of a series of shortened analogues of (KLAKLAK)2. They contain single [...] Read more.
(1) Background: (KLAKLAK)2 is a representative of the antimicrobial peptide group which also shows good anticancer properties. (2) Methods: Herein, we report synthesis using SPPS and characterization by HPLC/MS of a series of shortened analogues of (KLAKLAK)2. They contain single sequence KLAKLAK as C-terminal amides. In addition, substitution of some natural amino acids with unnatural β-Ala and nor-Leu is realized. In addition, these structures are conjugated with second pharmacophore with well proven anticancer properties 1,8-naphthalimide or caffeic acid. Cytotoxicity, antiproliferative effect and antimicrobial activity of newly synthesized structures were studied. (3) Results: The obtained experimental results reveal significant selective index for substances with common chemical structure KLβAKLβAK-NH2. The antibacterial properties of newly synthesized analogues at two different concentrations 10 μM and 20 μM, were tested against Gram-negative microorganisms Escherichia coli K12 407. Only two of the studied compounds KLAKLAK-NH2 and the one conjugated with second pharmacophore 1,8-naphthalimide and unnatural amino acid nor-Leu showed moderate activity against tested strains at concentration of 20 μM. (4) Conclusions: The obtained results reveal that the introducing of 1,8-naphthalimideGly- and Caf- increase the cytotoxicity and antiproliferative activity of the peptides but not their selectivity. Only two compounds KLAKLAK-NH2 and 1,8-naphthalimideGKnLAKnLAK-NH2 show moderate activity against Escherichia coli K12 at low concentration of 20 μM. Full article
(This article belongs to the Special Issue Advancement in Design and Synthesis of Novel Drug)
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