The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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We report two series of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesized compounds were tested against human (h) isoforms hCA I, hCA II, hCA VII, and hCA XII. The first series of compounds, 4-(3-(2-(4-substitued piperazin-1-yl)ethyl)ureido)benzenesulfonamides, showed low nanomolar inhibitory action against hCA II, being less effective against the other isoforms. The second series, 2-(4-substitued piperazin-1-yl)-N-(4-sulfamoylphenyl)acetamide derivatives, showed low nanomolar inhibitory activity against hCA II and hCA VII, isoforms involved in epileptogenesis. Some of these derivatives were evaluated for their anticonvulsant activity and displayed effective seizure protection against MES and scPTZ induced seizures in Swiss Albino mice. These sulfonamides were also found effective upon oral administration to Wistar rats and inhibited MES induced seizure episodes in this animal model of the disease. Some of the new compounds showed a long duration of action in the performed time course anticonvulsant studies, being nontoxic in subacute toxicity studies.

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(2013) Thermosensitive ion channel TRPV1 is endogenously expressed in the sperm of a fresh water teleost fish (Labeorohita) and regulates sperm motility, Channels, 7:6, 483-492,

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Surface measurements of O 3 , NO, NO 2 and NO x have been made over a semi-arid rural site, Anantapur (14.62°N; 77.65°E; 331 m asl) in southern India, during January-December 2010. The highest monthly mean O 3 concentration was observed in April (56.1 ± 9.9 ppbv) and the lowest in August (28.5 ± 7.4), with an annual mean of 40.7 ± 8.7 ppbv for the observation period. Seasonal variations in O 3 concentrations were the highest during the summer (70.2 ± 6.9 ppbv), and lowest during the monsoon season (20.0 ± 4.7 ppbv), with an annual mean of 40.7 ± 8.7 ppbv. In contrast, higher NO x values appeared in the winter (12.8 ± 0.8 ppbv) followed by the summer season (10.9 ± 0.7 ppbv), while lower values appeared in the monsoon season (3.7 ± 0.5 ppbv). The results for O 3 , NO and NO 2 indicate that the level of oxidant concentration ([OX] = NO 2 + O 3 ) at a given location is the sum of NO x -independent "regional contribution" (background level of O 3 ) and linearly NO x -dependent "local contribution". The O 3 concentration shows a significant positive correlation with temperature, and a negative correlation with both wind speed and relative humidity. In contrast, NO x have a significant positive correlation with humidity and wind speed, and negative correlation with temperature. The slope between [BC] and [O 3 ] suggests that every 1 μg/m 3 increase in black carbon aerosol mass concentration causes a reduction of 4.7 μg/m 3 in the surface ozone concentration. A comparative study using satellite data shows that annual mean values of tropospheric ozone contributes 12% of total ozone, while near surface ozone contributes 82% of tropospheric ozone. The monthly mean variation of tropospheric ozone is similar to that tropospheric NO 2 , with a correlation coefficient of +0.80.

Two series of novel benzenesulfonamide derivatives were synthesized and evaluated for their human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against four isoforms, hCA I, hCA II, hCA VII, and hCA IX. It was found that compounds of both series showed low to medium nanomolar inhibitory potential against all isoforms. Some of these derivatives displayed selective inhibition against the epileptogenesis related isoforms hCA II and VII, within the nanomolar range. These potent hCA II and VII inhibitors were evaluated as anticonvulsant agents against MES and sc-PTZ induced convulsions. These sulfonamides effectively abolished induced seizures in both models. Furthermore, time dependent seizure protection capability of the most potent compound was also evaluated. A long duration of action was displayed, with efficacy up to 6 h after drug administration. The compound appeared as an orally active anticonvulsant agent without showing neurotoxicity in a rotarod test, a nontoxic chemical profile being observed in subacute toxicity study.