Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatinase-B was desired. Previously published work with peptidyl hydroxamates and thiols indicated that while preparing gelatinase selective inhibitors was straightforward, there was not an obvious route to selective inhibitors of collagenase-1. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1 and gelatinase-B substrate hydrolysis. A method for estimating the IC50 values of compounds generated by high-throughput parallel synthesis aided in the identification of compounds with the desired properties. We have found that thiol diketopiperazines derived from nitrophenylalanine are both potent and selective inhibitors of collagenase-1. In addition, we have demonstrated that combinatorial chemistry can be utilized to identify molecules with a desired selectivity profile without access to the traditional tools of rational drug design.

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A comparative study of modern coupling reactions involving Boc‐protected amino acid derivatives and dipeptides with N‐terminal α,α–dialkylation and N‐methylation was carried out. The coupling reactions were run using either equimolar amounts of the amino and activated carboxyl components or an excess of the activated carboxyl component. Yields of the target tripeptide Boc‐Phe‐Xaa‐Phe‐OBzl (Xaa = (NMe)Ala, (NMe)Alb, or (NMe)αAc5c) were compared. Less than 10% of the product was obtained from methods utilizing pivaloyl mixed anhydride, pentafluorophenyl ester or acyl fluoride activation when Xaa = (NMe)Aib and (NMe)αcAc5c. At room temperature, significant yields of these two products were obtained from reactions which utilized an excess of the HBTU reagent (O‐benzotriazol‐1‐yl‐N,N,N′,N′‐tetramethyluronium hexafluorophosphate), the PyBroP reagent (bromo‐tris‐pyrrolidino‐phosphonium hexafluorophosphate) or Boc‐Phe‐NCA (Boc‐protected phenylalanine N‐carboxyanhydride). Moreover, the Boc‐Phe‐NCA method was superior when used over a prolonged reaction time or at elevated temperature.

Water-resource deficits have led to the need for artificial groundwater-recharge techniques to provide drinking water for rural communities in southeastern Kazakhstan, especially those with a small number of inhabitants. The Kishi-Tobe settlement located in the Karatal agricultural area on the right bank of the Karatal River in southeastern Kazakhstan has severe water-supply shortages. In this study, the groundwater-flow model MODFLOW was used to simulate complex hydrogeological and irrigation conditions for a quantitative assessment of artificial groundwater recharge from infiltration pools. The aim of these pools was to solve the water shortage in the Kishi-Tobe settlement. New findings showed that the maximum rate of artificial groundwater recharge from the infiltration pool can reach 1000 m 3 day −1 , corresponding to an infiltration rate of 0.2 m day −1 , which creates a groundwater mound with a radius of around 500 m from the center of the pool. The groundwater mound also serves as a hydrodynamic barrier, preventing inflow of contaminated groundwater from irrigated fields and rice checks to the pumping wells. The potential rate of groundwater pumping from two water-supply wells can reach up to 7350 m 3 day −1 over 10 years, providing a maximum drawdown in the wells of about 24 m. The water required by the Kishi-Tobe settlement can be supplied at a rate of 864 m 3 day −1 , achieving both available drawdowns by the end of the forecast period and balanced provision of the groundwater resource.

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