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Leishmania and Trypanosoma parasites are responsible for the challenging neglected tropical diseases leishmaniases, Chagas disease, and human African trypanosomiasis, which account for up to 40,000 deaths annually mainly in developing countries. Current chemotherapy relies on drugs with significant limitations in efficacy and safety, prompting the urgent need to explore innovative approaches to improve the drug discovery pipeline. The unique trypanothione-based redox pathway, which is absent in human hosts, is vital for all trypanosomatids and offers valuable opportunities to guide the rational development of specific, broad-spectrum and innovative anti-trypanosomatid agents. Major efforts focused on the key metabolic enzymes trypanothione synthetase-amidase and trypanothione reductase, whose inhibition should affect the entire pathway and, finally, parasite survival. Herein, we will report and comment on the most recent studies in the search for enzyme inhibitors, underlining the promising opportunities that have emerged so far to drive the exploration of future successful therapeutic approaches.

TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of TIBO R82913 (compounds 1) were inactive, whereas interesting results were obtained for truncated derivatives 2. Compound 2 w was the most potent among this series in cell-based assays (EC50=0.07 microM, CC50>200 microM, SI>2857). It was twofold less potent than R82913, but more selective. An X-ray crystallographic analysis was carried out to establish the absolute configuration of 2 w and its enantiomer 2 x, which were obtained by semipreparative HPLC of 2 v, one of the most potent racemates. Compounds 1-3 were proven to target HIV-1 RT. In fact, representative derivatives inhibited recombinant HIV-1 RT in vitro at concentrations similar to those active in cell-based assays. 3D QSAR studies and docking simulations were developed on TIBO- and TBO-like sulfone derivatives to rationalize their anti-HIV-1 potencies and to predict the activity of novel untested sulfone derivatives. Predictive 3D QSAR models were obtained with a receptor-based alignment by docking of TIBO- and TBO-like derivatives into the NNBS of RT.

A simple and efficient strategy to convert the racemic mixture of 8-chloro-2-(2,6-difluorophenylmethyl)-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide, a new anti-HIV-1 agent targeted to reverse transcriptase, into the more active (S)-enantiomer is described. The method utilizes repetition of the following two steps: 1) semipreparative enantioseparation by HPLC on chiral stationary phase; 2) base-induced racemization of the less active (R)-enantiomer.

A practical and versatile method for the synthesis of 2H-pyrrolo[3,4-b]quinolin-9(4H)-one skeleton via tosylmethyl isocyanide (TosMIC) reaction has been developed. Many attempts have been made to reverse the null reactivity of 4-hydroxyquinoline and its N-alkyl derivatives toward TosMIC reactant. For this reason various molecular modifications have been improved for the purpose of obtaining a reactive substrate. tert-Butyl-4-oxoquinoline-1(4H)-carboxylate resulted in the best substrate to provide the desired tricyclic system via facile TosMIC reaction.

Intramolecular cyclization of 1-(2-aminophenylsulfonyl)-1H-pyrrole-2-acetic acid 5 gave 10H-pyirolo[1,2-b][1,2,6]benzothiadiazocin-11(12H)-one 5,5-dioxide 4, a novel heterocyclic system of pyrrolobenzothiadiazocine family. Compound 5 was obtained starting from 2-nitrobenzenesulfonyl chloride with ethyl 1H-pyrrole-2-(α-oxo)acetate, which were condensed to afford 1-(2-nitrophenylsulfonyl)-1H-pyrrole-2-(α-oxo)acetate 13. Reduction of 13 gave the amino ester 7, which was hydrolyzed to the required aminoacid 5. The synthesis of 7-chloro-10H-pyrrolo[1,2-b][1,2,6]benzothiadiazocin-11(12H)-one 5,5-dioxide 16 is also described.

Summary Reaction of arylacetyl chlorides on thiophene or pyrrole derivatives furnished 2-aryl-1-(2-thienyl)- or 2-aryl-1-(1 H -pyrrol-2-yl)-1-ethanones. Reduction of ketones to the corresponding carbinols and reaction of the latter compounds with 1,1′-sulfonyldiimidazole or 1,1′-carbonyldiimidazole gave 2-thienyl- and 1 H -pyrrol-2-yl-1-aryl-2-( 1 H -imidazol-1-yl)ethanes, respectively. The new compounds were tested in vitro against a variety of pathogenic fungi in comparison with miconazole and bifonazole. Some 5-chloro-2-thienyl derivatives were endowed with good antifungal activity, particularly against Candida albicans and Cryptococcus neoformans .

The synthesis of derivatives of 2,3-dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-thione 1,1-dioxide is reported starting from N-substituted ethyl 2-(5-chloro-2-nitrobenzenesulfonamido)-2-alkyl-acetates. Fundamental steps of the synthetic pathway were: i) intramolecular cyclization of N-substituted 2-(2-amino-5-chlorobenzenesulfonamido)-2-alkylacetic acids in the presence of N-(3-dimethyl-aminopropyl)-N′-ethyl carbodiimide hydrochloride-N,N-dimethylaminopyridine complex; ii) building of imidazole ring from 2-alkyl-8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide to achieve 2-alkyl-9-chloro-2,3-dihydro-3-methylimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one 1,1-dioxide; iii) preparation of thiocarbonyl derivative by treatment with Lawesson's reagent. Introduction of a 3-methyl-2-butenyl chain at position 2 of above imidazobenzothiadiazepinone required protection at the 7 position with thermally removable tert-butoxycarbonyl moiety, due to the fact that alkylation of unprotected structure proved to be regioselective for the 7 position.