Synthesis of proline derived benzenesulfonamides: A potent anti-Trypanosoma brucei gambiense agent

• Published in: European journal of medicinal chemistry 2018-06, Vol.154, p.110-116
• Main Authors: Ugwu, David I., Okoro, Uchechukwu C., Mishra, Narendra K.
• Format: Article
• Language: English
• Subjects: African trypanosomiasis; Animals; Anti-inflammatory; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Benzenesulfonamides; Carboxamides; Carrageenan; Catalysis; Dose-Response Relationship, Drug; Edema - chemically induced; Edema - drug therapy; Male; Mice; Molecular Structure; Parasitic Sensitivity Tests; Proline - chemical synthesis; Proline - chemistry; Proline - pharmacology; Rats; Structure-Activity Relationship; Sulfonamides; Sulfonamides - chemistry; Sulfonamides - pharmacology; Trypanosoma brucei gambiense - drug effects; Trypanosome brucei
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.05.017

Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight new carboxamide derivatives bearing substituted benzenesulfonamides. The base promoted reactions of l-proline and L-4-hydroxyproline with substituted benzenesulfonyl chlorides gave the benzenesulfonamides (11a-h) in excellent yields. Boric acid mediated amidation of the benzenesulfonamides (11a-h) and p-aminobenzoic acid (12) gave the new carboxamides (13a-h) in excellent yields. The new carboxamides were tested for their antitrypanosomal and anti-inflammatory activities against Trypanosome brucei gambiense and inhibition of carrageenan-induced rat paw edema. Compound 13f was the most potent antitrypanosomal agent with an IC50 value of 2 nM as against 5 nM for melarsoprol; whereas compound 13a was the most potent anti-inflammatory agent with percentage inhibition of carrageenan-induced rat paw edema of 58, 60, 67 and 84% after 0.5 h, 1 h, 2 h and 3 h administration respectively. The structure-activity relationship study revealed that substitution at the para position in the benzenesulfonamide ring increased both the antitrypanosomal and anti-inflammatory activities. The 4-hydroxyprolines (13a-d) showed higher anti-inflammatory activity than the prolines (13e-h). In contrast, the prolines (13e-h) had higher antitrypanosomal activities than the 4-hydroxyprolines. The link between excessive sleep and inflammation makes the report of this class of compounds possessing both antitrypanosomal and anti-inflammatory activity worthwhile. The pharmacokinetic studies showed that the compounds would not pose oral bioavailability, transport and permeability problems. [Display omitted] •Structure-based design and synthesis of novel proline derived sulphonamides is reported.•There is a need for the synthesis of antitrypanosomal agents with additional anti-inflammatory properties.•The reported compounds possessed good antitrypanosomal and anti-inflammatory activities.•Physicochemical properties prediction was carried out on the reported compounds to assess their pharmacokinetic profile.