Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

Abstract

Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure–activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure–metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.

Discovery of diarylpyrimidine derivatives bearing piperazine sulfonyl as potent HIV-1 nonnucleoside reverse transcriptase inhibitors

“…g Used for comparison. The data were obtained from the same laboratory using the same method (Prof. Christophe Pannecouque, Rega Institute for Medical Research, KU Leuven, Belgium) 7 .…”

“…As shown in Fig. 1 , Nevirapine (NVP, 1 ), efavirenz (EFV, 2 ), etravirine (ETR, 3 ), rilpivirine (RPV, 4 ) and doravirine (DOR, 5 ) are NNRTIs that have been approved by the U.S. FDA for the treatment of AIDS 7 . NNRTIs have a relatively low genetic barrier because of their allosteric binding, which leads to rapid emergence of drug-resistant strains during their clinical applications 8 .…”

Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

“…Undoubtedly, our endeavors and most achievements in antiviral drug research field have continuously benefited from the inspiration of these articles and his direct guidance. Our long-term close cooperation with Professor Erik De Clercq culminated in the discovery of several antiviral drug candidates for further preclinical studies or clinical trials [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. On the occasion of his 80th anniversary, on behalf of our whole research group, we would like to extend our sincere gratitude and best wishes to Professor Erik De Clercq.…”

Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties

“…The DAPY class typically suffers from poor aqueous solubility, which can contribute to low bioavailability and drug-like properties. Hence, the development of novel DAPY-like inhibitors with high potency against the WT virus and resistant viral strains, as well as improved aqueous solubility, is highly desirable. − Numerous publications ,− and reviews ,, on DAPY NNRTIs have been recently published. In several cases, another (hetero)­cycle was attached to the pyrimidine central core of molecules to form fused bicyclic NNRTIs in order to explore the entrance channel of the NNRTI binding pocket. ,,, In our current work, we decided to substitute the pyrimidine core of ETV and RPV (Figure ) with modified bicyclic cores in order to introduce an additional polar moiety, which should result in increased aqueous solubility.…”

“…Hence, the development of novel DAPY-like inhibitors with high potency against the WT virus and resistant viral strains, as well as improved aqueous solubility, is highly desirable. − Numerous publications ,− and reviews ,, on DAPY NNRTIs have been recently published. In several cases, another (hetero)­cycle was attached to the pyrimidine central core of molecules to form fused bicyclic NNRTIs in order to explore the entrance channel of the NNRTI binding pocket. ,,, In our current work, we decided to substitute the pyrimidine core of ETV and RPV (Figure ) with modified bicyclic cores in order to introduce an additional polar moiety, which should result in increased aqueous solubility. Furthermore, the second ring (ring B) of the bicyclic cores may also prove advantageous from the conformational viewpoint: it is expected to lock the inhibitors in the desirable U-shape to introduce potency (especially for the six-membered analogues), while not being aromatic, it still keeps certain flexibility to accommodate changes in the binding pocket (to preserve the resistance profile).…”