Lester A. Mitscher

The Organic Chemistry of Drug Synthesis

The Organic Chemistry of Drug Synthesis , The Organic Chemistry of Drug Synthesis , کتابخانه دیجیتال جندی شاپور اهواز

Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)

The objective of the glossary is to provide in a single document a consistent terminology and concise definitions of terms covering the various aspects of medicinal chemistry. This was felt necessary with regard to the rapid changes occuring in medicinal chemistry and also by the need to establish international definition standards. Effectively the possibility exists that in different countries certain terms may not have the same meaning, in such a case the creation of an internationally accepted definition is particularly justified. A Working Party belonging to the IUPAC Section on Medicinal Chemistry has therefore been assembled which prepared the present glossary. Concise but sufficiently explanatory definitions have been formulated for about one hundred commonly employed terms which can be considered of particular interest to the medicinal chemistry community. The glossary has been compiled in part from definitions proposed by the Working Party in part from earlier IUPAC glossaries and in part from well-accepted definitions taken from the literature but which were sometimes published in journals or books that may not be readily accessible. ALPHABETICAL ORDERED ENTRIES The glossary has been compiled in part from definitions proposed by the Working Party and in part from well-accepted definitions taken from the literature. In most cases, definitions given here are for specific areas of medicinal chemistry. Some definitions taken from the Glossary for Chemists of Terms Used in Biotechnology (Pure Appl. Chem., 1992, 64, 143-168) were also included, eventually in a slightly modified form; they are identified by an asterisk*. Others, which appear in the Glossary on Computational Drug Design (Pure Appl. Chem., 1997, 69, 1137-1 152) and in Glossary for Chemists of terms used in Toxicology (Pure Appl. Chem. 1993,65,2003-2122), are identified by a double** and a triple*** asterisk respectively. Active transport* Active transport is the carriage of a solute across a biological membrane from low to high concentration that requires the expenditure of (metabolic) energy. Address-message concept Address-message concept refers to compounds in which part of the molecule is required for binding (address) and part for the biological action (message). ADME Abbreviation for Absorption, Distribution, Metabolism, Excretion. (See also Pharmacokinetics; Drug disposition). Affinity Affinity is the tendency of a molecule to associate with another. The affinity of a drug is its ability to bind to its biological target (receptor, enzyme, transport system, etc.) For pharmacological receptors it can be thought of as the frequency with which the drug, when brought into the proximity of a receptor by diffusion, will reside at a position of minimum free energy within the force field of that receptor. 1130

The 2-pyridone antibacterial agents: bacterial topoisomerase inhibitors.

Many attempts have been made to prepare analogs of 4‐quinolone antibacterial agents bearing novel ring systems, which might retain the favorable properties of these widely used antibacterial agents and at the same time increase activity against multidrug‐resistant bacteria, streptococci, and anaerobic microorganisms. One such attempt involved bioisosteric exchange of the 1‐N atom and 4a‐C atom of naphthyridones, quinolones, and benzoxazines to produce a family of highly active pyridopyrimidines, quinolizines, and ofloxacin bioisosteres. These new antibacterial agents have been named collectively as the 2‐pyridones. Many hundreds of 2‐pyridones have been synthesized and evaluated in vitro and in vivo, and selected members are advancing toward human clinical trials. Preparation of these bioisosteres required the development of enabling chemistry, as previous methods were unsuccessful in producing the needed core structures. This review compares the structure‐activity relationships of these agents with known trends among 4‐quinolones, from which it is seen that there are many parallels, but also some significant departures as well. Generally, 2‐pyridones are more highly active in vitro and in vivo and more water soluble than comparable 4‐quinolones. These properties are posited to arise from electronic and conformational alternations in these new substances. Selected members show excellent pharmacodynamic properties, justifying the view that this is a very promising new class of totally synthetic antibacterial agents.

Natural antimutagenic agents

Following a brief review of recent discoveries in the field of natural antimutagenic and tumor chemopreventive agents, contemporary findings in the authors laboratories employing the direct acting mutagen, ethyl methanesulfonate, in modified Ames tests and eukaryotic murine FM3A mammary tumor cells modified to be subject to thymidine-less death are described to illustrate the underlying principles. The EMS studies are illustrated with the isolation of the novel antimutagen, plicatin B, from the medicinal plants, Psoralea juncaea and P. plicata. The FM3A studies are carried out with extracts of Styrax asiatica, a plant previously studied extensively with the EMS system. The FM3A findings closely parallel the earlier work with EMS showing that the responsible agents, cinnamic acid, cinnamoyl ricinoleate and cinnamoyl cinnamate are effective both in prokaryotic and eukaryotic tests and that the new FM3A assay system has useful properties for screening and assay of novel antimutagenic agents.

Multiple drug resistance

Multiple drug resistance to antibacterial agents, antifungals, antivirals, antiprotozoals, and antitumor agents has risen spectacularly in the last decade or so and presently threatens eventually to put an end to successful chemotherapy in all of the above fields. This review summarizes the known origins of the problem, its present dimensions, the means employed to combat the phenomenon and promising avenues for future developments.

Tuberculosis: A search for novel therapy starting with natural products

The reemergence of tuberculosis and closely related diseases as significant public health problems is briefly reviewed with particular emphasis on the exacerbating role of AIDS and multiple drug resistance. Screening methods available for discovering new chemical entities active against resistant strains are discussed and their use in screening extracts and compounds for activity is illustrated with a number of newly discovered structures being presented. In particular, the properties of the potent and structurally novel indoloquinazolinone alkaloid, tryptanthrin, is described. Many analogs of this lead structure were synthesized by combinatorial and multiple parallel synthetic techniques and evaluated in vitro and in vivo for their potential in the chemotherapy of human infections.

The search for orally active medications through combinatorial chemistry

The literature of combinatorial chemistry is reviewed with particular attention paid to considerations of absorption, distribution, metabolism and excretion in the design and evaluation of libraries containing drug‐like molecules. Published libraries are evaluated in particular for the likelihood that the products would possess oral bioavailability.

Amorfrutin A and B, bibenzyl antimicrobial agents from Amorpha fruticosa

Abstract Bioassay directed fractionation of the waxy fractions derived from the fruit of Amorpha fruticosa resulted in the isolation of amorfrutin A and B, active new antimicrobial agents. Spectroscopic studies, chemical degradation and synthesis showed them to be new bibenzyl metabolites.

Antimutagenic activity of extracts of leaves of four common edible vegetable plants in Nigeria (west Africa).

Organic solvent extracts of leaves of 4 common edible vegetable plants--Bryophyllum pinnatum, Dialium guincense, Ocimum gratissimum and Vernonia amygdalina--had inhibitory activity for His- to His+ reverse-mutations induced by ethyl methanesulfonate acting on Salmonella typhimurium TA100. The concentrated ethyl acetate, methanol and petroleum ether extracts were heat-stable when dissolved in dimethyl sulfoxide. The Bryophyllum ethyl acetate extract was fractionated into alkaloidal/water-soluble, acids, polar lipid and non-polar lipid fractions. The polar and non-polar lipid fractions inhibited reversion mutations induced by ethyl methanesulfonate acting on TA100 or TA102, and were also active against reversions induced by 4-nitro-O-phenylenediamine and 2-aminofluorene in TA98. The alkaloidal/water-soluble and the acid fractions had no appreciable antimutagenic activities.

Antimicrobial pterocarpans of nigerian Erythrina mildbraedii

Abstract Bioassay-directed fractionation of ethanolic extracts of the roots of Erythrina mildbraedii , a plant used in the indigenous system of medicine in Nigeria, resulted in the isolation of the previously known pterocarpans erythrabyssin-II and isoneorautenol and the new pterocarpans erybraedins A, B, and C. The structures of the new compounds were determined by chemical transformations and/or spectroscopy and their in vitro antimicrobial spectra and potencies are reported.