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Design, Synthesis, and Analysis of Potential Drugs

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 21483

Special Issue Editor


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Guest Editor
Department of Organic Chemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, The Medical University of Silesia in Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland
Interests: organic synthesis; heterocycles; dipyridothiazines; structural analysis; lipophylicity; SAR
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Special Issue Information

Dear Colleagues,

One of the major challenges of modern medicine is the effective treatment of many diseases that are still difficult to manage. Despite the commercial availability of a number of therapeutics, their performance is still largely limited. The improvement of patients’ chances for recovery is pursued by searching new compounds with specific biological properties, which could become an alternative or a breakthrough therapy. On the other hand, we are witnessing the dynamic development of chemistry, medicinal chemistry, and biochemistry, which are presenting new and innovative solutions for drug discovery.

The present Special Issue “Design, Synthesis, and Analysis of Potential Drugs” aims to highlight the most interesting studies in the field of design of bioactive molecules that could become effective drugs. Moreover, of interest will be studies dealing with the processes of biotransformation of organic compounds and organic synthesis of pharmaceutical compounds. In addition, it is expected that the chemistry of heterocycles, carbohydrates, and proteins—enzymes in particular—will also be described and discussed in the submitted papers.

I hope that the proposed Special Issue will offer a comprehensive and interesting view of the current research on new potential drugs and be an important source of successful solutions for their modern design.

Prof. Dr. Beata Morak-Młodawska
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

  • Organic synthesis of bioactive compounds
  • Structural analysis
  • Biological activity of organic molecules
  • Pharmacokinetic analysis of potential drug
  • Lipophilicity
  • Active pharmaceutical ingredients

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Published Papers (7 papers)

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Research

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11 pages, 1166 KiB  
Article
Lipophilicity and Pharmacokinetic Properties of New Anticancer Dipyridothiazine with 1,2,3-Triazole Substituents
by Beata Morak-Młodawska and Małgorzata Jeleń
Molecules 2022, 27(4), 1253; https://doi.org/10.3390/molecules27041253 - 13 Feb 2022
Cited by 6 | Viewed by 2669
Abstract
The lipophilicity parameters (logPcalcd, RM0 and logPTLC) of 10 new active anticancer dipirydothiazines with a 1,2,3-triazole ring were determined theoretically using computational methods and experimentally by reversed-phase TLC. Experimental lipophilicity was assessed using mobile phases [...] Read more.
The lipophilicity parameters (logPcalcd, RM0 and logPTLC) of 10 new active anticancer dipirydothiazines with a 1,2,3-triazole ring were determined theoretically using computational methods and experimentally by reversed-phase TLC. Experimental lipophilicity was assessed using mobile phases (a mixture of TRIS buffer and acetone) using a linear correlation between the RM retention parameter and the volume of acetone. The RM0 parameter was correlated with the specific hydrophobic surface b, revealing two congenerative subgroups: 1,2,3-triazole-1,6-diazaphenothiazines and 1,2,3-triazole-1,8-diazaphenothiazines hybrids. The RM0 parameter was converted into the logPTLC lipophilicity parameter using a calibration curve. The investigated compounds appeared to be moderately lipophilic. Lipophilicity has been compared with molecular descriptors and ADME properties. The new derivatives followed Lipinski’s, Ghose’s and Veber’s rules. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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13 pages, 794 KiB  
Article
A Comparative Study of the Lipophilicity of Metformin and Phenformin
by Małgorzata Dołowy, Josef Jampilek and Katarzyna Bober-Majnusz
Molecules 2021, 26(21), 6613; https://doi.org/10.3390/molecules26216613 - 31 Oct 2021
Cited by 10 | Viewed by 2482
Abstract
The results presented in this paper confirm the beneficial role of an easy-to-use and low-cost thin-layer chromatography (TLC) technique for describing the retention behavior and the experimental lipophilicity parameter of two biguanide derivatives, metformin and phenformin, in both normal-phase (NP) and reversed-phase (RP) [...] Read more.
The results presented in this paper confirm the beneficial role of an easy-to-use and low-cost thin-layer chromatography (TLC) technique for describing the retention behavior and the experimental lipophilicity parameter of two biguanide derivatives, metformin and phenformin, in both normal-phase (NP) and reversed-phase (RP) TLC systems. The retention parameters (RF, RM) obtained under different chromatographic conditions, i.e., various stationary and mobile phases in the NP-TLC and RP-TLC systems, were used to determine the lipophilicity parameter (RMW) of metformin and phenformin. This study confirms the poor lipophilicity of both metformin and phenformin. It can be stated that the optimization of chromatographic conditions, i.e., the kind of stationary phase and the composition of mobile phase, was needed to obtain the reliable value of the chromatographic lipophilicity parameter (RMW) in this study. The fewer differences in the RMW values of both biguanide derivatives were ensured by the RP-TLC system composed of RP2, RP18, and RP18W plates and the mixture composed of methanol, propan-1-ol, and acetonitrile as an organic modifier compared to the NP-TLC analysis. The new calculation procedures for logP of drugs based on topological indices 0χν, 0χ, 1χν, M, and Mν may be a certain alternative to other algorithms as well as the TLC procedure performed under optimized chromatographic conditions. The knowledge of different lipophilicity parameters of the studied biguanides can be useful in the future design of novel and more therapeutically effective metformin and phenformin formulations for antidiabetic and possible anticancer treatment. Moreover, the topological indices presented in this work may be further used in the QSAR study of the examined biguanides. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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13 pages, 883 KiB  
Article
Synthesis of Functionalized Diethyl(pyrrolidin-2-yl)phosphonate and Diethyl(5-oxopyrrolidin-2-yl)phosphonate
by Iwona E. Głowacka, Anna Hartwich, Iwona Rozpara and Dorota G. Piotrowska
Molecules 2021, 26(11), 3160; https://doi.org/10.3390/molecules26113160 - 25 May 2021
Cited by 1 | Viewed by 1982
Abstract
Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O [...] Read more.
Short and efficient syntheses of functionalized (pyrrolidin-2-yl)phosphonate and (5-oxopyrrolidin-2-yl)phosphonate have been developed. The synthetic strategy involved the diastereospecific 1,3-dipolar cycloaddition of N-benzyl-C-(diethoxyphosphoryl)nitrone to cis-1,4-dihydroxybut-2-ene and dimethyl maleate, respectively. O,O-Diethyl 3-carbamoyl-4-hydroxy(5-oxopyrrolidin-2-yl)phosphonate was obtained from O,O-diethyl 2-benzyl-4,5-dimethoxycarbonyl(isoxazolidin-3-yl)phosphonate by hydrogenation and subsequent treatment with ammonia, whereas transformation of O,O-diethyl 2-benzyl-4,5-dihydroxymethyl(isoxazolidin-3-yl)phosphonate into O,O-diethyl 3-aminomethyl-4-hydroxy(pyrrolidin-2-yl)phosphonate was accomplished by mesylation followed by hydrogenolysis to undergo intramolecular cyclization and the introduction of amino group via ammonolysis. Stereochemistry of the isoxazolidine cycloadducts, as well as the final functionalized (pyrrolidin-2-yl)- and (5-oxopyrrolidin-2-yl)phosphonates were established based on conformational analyses using vicinal H–H, H–P, and C–P couplings and supported by the observed diagnostic NOESY correlation signals. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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19 pages, 2197 KiB  
Article
Synthesis, Characterization and In Vitro Evaluation of Novel 5-Ene-thiazolo[3,2-b][1,2,4]triazole-6(5H)-ones as Possible Anticancer Agents
by Serhii Holota, Sergiy Komykhov, Stepan Sysak, Andrzej Gzella, Andriy Cherkas and Roman Lesyk
Molecules 2021, 26(4), 1162; https://doi.org/10.3390/molecules26041162 - 22 Feb 2021
Cited by 17 | Viewed by 3672
Abstract
The present paper is devoted to the search for drug-like molecules with anticancer properties using the thiazolo[3,2-b][1,2,4]triazole-6-one scaffold. A series of 24 novel thiazolo-[3,2-b][1,2,4]triazole-6-ones with 5-aryl(heteryl)idene- and 5-aminomethylidene-moieties has been synthesized employing three-component and three-stage synthetic protocols. A mixture [...] Read more.
The present paper is devoted to the search for drug-like molecules with anticancer properties using the thiazolo[3,2-b][1,2,4]triazole-6-one scaffold. A series of 24 novel thiazolo-[3,2-b][1,2,4]triazole-6-ones with 5-aryl(heteryl)idene- and 5-aminomethylidene-moieties has been synthesized employing three-component and three-stage synthetic protocols. A mixture of Z/E-isomers was obtained in solution for the synthesized 5-aminomethylidene-thiazolo[3,2-b]-[1,2,4]triazole-6-ones. The compounds have been studied for their antitumor activity in the NCI 60 lines screen. Some compounds present excellent anticancer properties at 10 μM. Derivatives 2h and 2i were the most active against cancer cell lines without causing toxicity to normal somatic (HEK293) cells. A preliminary SAR study had been performed for the synthesized compounds. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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18 pages, 2573 KiB  
Article
New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies
by Zbigniew Karczmarzyk, Marta Swatko-Ossor, Waldemar Wysocki, Monika Drozd, Grazyna Ginalska, Anna Pachuta-Stec and Monika Pitucha
Molecules 2020, 25(24), 6033; https://doi.org/10.3390/molecules25246033 - 19 Dec 2020
Cited by 32 | Viewed by 3470
Abstract
A series of 1,2,4-triazole derivatives were synthesized and assigned as potential anti-tuberculosis substances. The molecular and crystal structures for the model compounds C1, C12, and C13 were determined using X-ray analysis. The X-ray investigation confirmed the synthesis pathway and the assumed molecular structures [...] Read more.
A series of 1,2,4-triazole derivatives were synthesized and assigned as potential anti-tuberculosis substances. The molecular and crystal structures for the model compounds C1, C12, and C13 were determined using X-ray analysis. The X-ray investigation confirmed the synthesis pathway and the assumed molecular structures for analyzed 1,2,4-triazol-5-thione derivatives. The conformational preferences resulting from rotational degrees of freedom of the 1,2,4-triazole ring substituents were characterized. The lipophilicity (logP) and electronic parameters as the energy of frontier orbitals, dipole moments, NBO net charge distribution on the atoms, and electrostatic potential distribution for all structures were calculated at AM1 and DFT/B3LYP/6-311++G(d,p) level. The in vitro test was done against M. tuberculosis H37Ra, M. phlei, M. smegmatis, and M. timereck. The obtained results clearly confirmed the antituberculosis potential of compound C4, which turned out to be the most active against Mycobacterium H37Ra (MIC = 0.976 μg/mL), Mycobaterium pheli (MIC = 7.81 μg/mL) and Mycobacerium timereck (62.6 μg/mL). Satisfactory results were obtained with compounds C8, C11, C14 versus Myc. H37Ra, Myc. pheli, Myc. timereck (MIC = 31.25−62.5 μg/mL). The molecular docking studies were carried out for all investigated compounds using the Mycobacterium tuberculosis cytochrome P450 CYP121 enzyme as molecular a target connected with antimycobacterial activity. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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8 pages, 1160 KiB  
Communication
Pharmacological Inhibition of CDK8 in Triple-Negative Breast Cancer Cell Line MDA-MB-468 Increases E2F1 Protein, Induces Phosphorylation of STAT3 and Apoptosis
by Jensen M. Spear, Zhixin Lu and Wade A. Russu
Molecules 2020, 25(23), 5728; https://doi.org/10.3390/molecules25235728 - 4 Dec 2020
Cited by 7 | Viewed by 2952
Abstract
Cyclin-dependent kinase 8 (CDK8) has been identified as a colon cancer oncogene. Since this initial observation, CDK8 has been implicated as a potential driver of other cancers including acute myelogenous leukemia (AML) and some breast cancers. Here, we observed different biological responses to [...] Read more.
Cyclin-dependent kinase 8 (CDK8) has been identified as a colon cancer oncogene. Since this initial observation, CDK8 has been implicated as a potential driver of other cancers including acute myelogenous leukemia (AML) and some breast cancers. Here, we observed different biological responses to CDK8 inhibition among colon cancer cell lines and the triple-negative breast cancer (TNBC) cell line MDA-MB-468. When treated with CDK8 inhibitor 4, all treated cell lines responded with decreased cell viability and increased apoptosis. In the MDA-MB-468 cell line, the decrease in cell viability was dependent on increased phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is not observed in the colon cancer cell lines. Furthermore, increased STAT3 phosphorylation in 4 treated MDA-MB-468 cells was dependent on increased transcription factor E2F1 protein. These results are consistent with previous reports of exogenous expression of E2F1-induced apoptosis in MDA-MB-468 cells. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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Review

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24 pages, 3688 KiB  
Review
Selected β2-, β3- and β2,3-Amino Acid Heterocyclic Derivatives and Their Biological Perspective
by Urszula Bąchor and Marcin Mączyński
Molecules 2021, 26(2), 438; https://doi.org/10.3390/molecules26020438 - 15 Jan 2021
Cited by 7 | Viewed by 2958
Abstract
Heterocyclic moieties, especially five and six-membered rings containing nitrogen, oxygen or sulfur atoms, are broadly distributed in nature. Among them, synthetic and natural alike are pharmacologically active compounds and have always been at the forefront of attention due to their pharmacological properties. Heterocycles [...] Read more.
Heterocyclic moieties, especially five and six-membered rings containing nitrogen, oxygen or sulfur atoms, are broadly distributed in nature. Among them, synthetic and natural alike are pharmacologically active compounds and have always been at the forefront of attention due to their pharmacological properties. Heterocycles can be divided into different groups based on the presence of characteristic structural motifs. The presence of β-amino acid and heterocyclic core in one compound is very interesting; additionally, it very often plays a vital role in their biological activity. Usually, such compounds are not considered to be chemicals containing a β-amino acid motif; however, considering them as this class of compounds may open new routes of their preparation and application as new drug precursors or even drugs. The possibility of their application as nonproteinogenic amino acid residues in peptide or peptide derivatives synthesis to prepare a new class of compounds is also promising. This review highlights the actual state of knowledge about β-amino acid moiety-containing heterocycles presenting antiviral, anti-inflammatory, antibacterial compounds, anaplastic lymphoma kinase (ALK) inhibitors, as well as agonist and antagonists of the receptors. Full article
(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs)
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