Novel Structures of Uracil Mustard (Uramustine) Retaining Cytotoxic Activity and Drug-likeness for Oral Administration | Chapter 16 | New Insights into Disease and Pathogen Research Vol. 2

Aims: To present 12 new variants of uracil mustard having drug-like properties and cytotoxic functional group, by utilizing uracil mustard (uramustine) as a lead compound. Utilize rigorous substructure and similarity of a molecular scaffold to determine drug like variants. Physicochemical properties determined indicate the variants have favorable drug-likeness.

Study Design: Conduct molecular database search utilizing features of substructure and similarity based upon uracil mustard.

Place and Duration of Study: Department of Chemistry, Medicinal Chemistry Study Section, University of Nebraska at Omaha, Omaha Nebraska between January 2015 to March 2015.

Methodology: Uracil mustard consists of the pyrimidine derivative uracil, having the bifunctional nitrogen mustard cytotoxic moiety covalently bonded onto the ring. A systematic search, utilizing substructure component and similarity, within an in-silico database search successfully determined 12 variants. Rigorous criteria for drug-likeness were implemented to screen potential candidates that included the application of the Rule of 5. In addition, maintaining the cytotoxic moiety of nitrogen mustard was crucial.

Results: A total of 12 variants of uracil mustard was identified after an extensive molecular database search using rigorous criteria. All 12 variants, and including uracil mustard, showed zero violations of the Rule of 5, thereby indicating favorable drug-likeness. Values of polar surface area for all compounds at less than 80 Angstroms2 are suitable for central nervous system penetration. Polar surface area, number of atoms, and Log P for all compounds increased as the molecular weight increases. Structure substituents include nitrogen mustard groups, hydroxyl, alkyl and carbonyl moieties. Cluster analysis discerned greatest similarity among members of this group.

Conclusion: Applying rigorous search criteria within a molecular data base, for comparison and reject, successfully identified 12 variants of uracil mustard that show favorable drug-likeness in addition to cytotoxic capability. The design of new antitumor agents is important for increasing efficacy of the clinical treatment of cancer. Variation of physicochemical properties can benefit the efficacy of anticancer drugs and should be further investigated for the benefit of patients.

Author(s) Details

Dr. Ronald Bartzatt
Durham Science Center, University of Nebraska, 6001 Dodge Street, Omaha, Nebraska 68182, USA.

Read full article: http://bp.bookpi.org/index.php/bpi/catalog/view/71/860/660-1
View Volume: https://doi.org/10.9734/bpi/nidpr/v2

Structure, Properties, and Drug-likeness of Pharmaceuticals That Inhibit Ebola Virus Disease (EVD) Proliferation | Chapter 01 | Current Trends in Disease and Health Vol. 1

Introduction: The Ebola virus is one of known viruses within the genus Ebolavirus that are generally considered to cause Ebola virus disease (EBV) in humans. Some investigators have determined that Ebola virus outbreaks have an increased likelihood to occur when temperatures are lower and humidity is higher. The determination and evaluation of pharmacokinetic and pharmacodynamics properties of drugs potentially useful for treatment of Ebola virus disease is a very important consideration for discovery of new pharmaceuticals.

Aims: To present the molecular structures of compounds that has been shown to inhibit the proliferation of Ebola virus. To elucidate the molecular properties of these virus inhibiting compounds.

Study Design: The molecular properties of virus inhibiting compounds are elucidated and compiled. Pattern recognition methods and statistical analysis are applied to determine optimal properties of this group of compounds.

Place and Duration of Study: Chemistry Department, Durham Science Center, University of Nebraska, Omaha NE. between December 2015 and February 2016.

Methodology: A total of 60 compounds were identified as inhibiting the virus Ebola. The molecular properties such as Log P, molecular weight, and 7 other descriptors were elucidated utilizing heuristic methods. Structures are compared by applying classification methods with statistical tests to determine trends, underlying relationships, and pattern recognition.

Results: For 60 compounds identified the averages determined: for Log P (3.51), polar surface area (89.45 Angstroms2), molecular weight (432.6), molecular volume (393.96 Angstroms3), and number of rotatable bonds (7). Molecular weight showed a strong positive correlation to number of oxygen and nitrogen atoms, number of rotatable bonds, and molecular volume. K-means clustering indicated seven clusters divided according to highest similarity of members in the cluster. Ranges found: formula weights (157.1 to 822.94), Log P (-2.24 to 8.93), polar surface area (6.48 to 267.04 A2), and number of atoms (11 to 58). Multiple regression analysis produced an algorithm to predict similar compounds.

Conclusion: The formula weights and Log P values of Ebola virus inhibitors show a broad range in numerical values. Consistency in properties was identified by statistical analysis with grouping for similarity by K-means pattern recognition. Multiple regression analysis enables prediction of similar compounds as drug candidates. Only 29 compounds showed zero violations of rule of 5, an indication of favorable drug-likeness. These compounds are highly varied in structures and properties.

Author(s) Details

Dr. Ronald Bartzatt
University of Nebraska, Durham Science Center, 6001 Dodge Street, Omaha, Nebraska 68182, USA.

Read full article: http://bp.bookpi.org/index.php/bpi/catalog/view/59/640/520-1

View Volume: https://doi.org/10.9734/bpi/ctdah/v1