Lead compounds undesirable functionalities

Many chemical functionalities have been identified as undesirable in a lead compound. Compounds that have reactive electrophilic functional groups can form covalent bonds with proteins and will generate false positives in screening or may appear to be toxic. Such compounds should be excluded from the screening library. An example... 

When a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate. These may include undesirable side effects, physicochemical properties, other factors that affect oral bioavailability (see Chapter 9), and adverse metabolic or excretion properties. These undesirable properties could be the result of specific functional groups in the molecule. The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric replacement, or bioisosteric replacement. ... 

Full details of the reductive power of 9-borabicyclo[3,3,l]nonane have appeared and the susceptibility to reduction of aldehyde, ketone, and a number of other functional groups has been reviewed. Since tetra-n-butylammonium borohydride in dichloromethane reduces organic compounds with the same selectivity exhibited by sodium borohydride in aqueous or alcoholic media, the former system might prove the reagent of choice in those cases in which the use of protic solvents would lead to undesirable side-reactions. ... 

The water solubilities of the functional comonomers are reasonably high since they are usually polar compounds. Therefore, the initiation in the water phase may be too rapid when the initiator or the comonomer concentration is high. In such a case, the particle growth stage cannot be suppressed by the diffusion capture mechanism and the solution or dispersion polymerization of the functional comonomer within water phase may accompany the emulsion copolymerization reaction. This leads to the formation of polymeric products in the form of particle, aggregate, or soluble polymer with different compositions and molecular weights. The yield for the incorporation of functional comonomer into the uniform polymeric particles may be low since some of the functional comonomer may polymerize by an undesired mechanism. 

These supported cycloadducts were then treated with a base (LiOH, NaOH) in a mixture of water and alcohol to give the expected free acid derivatives. However, while the latter compounds were readily recovered, the same was not true for the ionic liquid 4b, which was obtained as a dark brown liquid impure by NMR analysis. Very likely, the basic hydrolysis of the ester function caused the deprotonation of the imidazolium ring leading to a series of undesired side-reactions. Therefore, milder reaction conditions were explored to cleave the Diels-Alder product from the ionic liquid support. Handy and Okello found that the best method was the cyanide-mediated transesterification that gave the corresponding methyl esters 9-11 and allowed recover of 4b in at least 90% yield. It was also demonstrated that the recovered 4b could be used for further supported syntheses. In fact, in two subsequent mns the yields of the final ester compound were similar, indicating that the ionic liquid 4b could be efficiently recycled. 

Other factors indicated m the data of Tables 1 and 2 include Pour Point—defined as the lowest temperature at which the material will pour and a function of the composition of the oil in terms of waxiness and bitumen content Salt Content—which is not confined to sodium chloride, but usually is interpreted in terms of NaCl Salt is undesirable because of the tendency to obstruct fluid flow, to accumulate as an undesirable constituent of residual oils and asphalts, and a tendency of certain salt compounds to decompose when heated, causing corrosion of refining equipment Metals Content—heavy metals, such as vanadium, nickel, and iron, tend to accumulate in the heavier gas oil and residuum fractions where the metals may interfere with refining operations, particularly by poisoning catalysts. The heavy metals also contribute to the formation of deposits on heated surfaces in furnaces and boiler fireboxes, leading to permanent failure of equrpment, interference with heat-transfer efficiency, and increased maintenance. 

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